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Role of emerging vitamin K‑dependent proteins: Growth arrest‑specific protein 6, Gla‑rich protein and periostin (Review)

  • Authors:
    • Huiyu Xiao
    • Jiepeng Chen
    • Lili Duan
    • Shuzhuang Li
  • View Affiliations

  • Published online on: December 29, 2020
  • Article Number: 2
  • Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Vitamin K‑dependent proteins (VKDPs) are a group of proteins that need vitamin K to conduct carboxylation. Thus far, scholars have identified a total of 17 VKDPs in the human body. In this review, we summarize three important emerging VKDPs: Growth arrest‑specific protein 6 (Gas 6), Gla‑rich protein (GRP) and periostin in terms of their functions in physiological and pathological conditions. As examples, carboxylated Gas 6 and GRP effectively protect blood vessels from calcification, Gas 6 protects from acute kidney injury and is involved in chronic kidney disease, GRP contributes to bone homeostasis and delays the progression of osteoarthritis, and periostin is involved in all phases of fracture healing and assists myocardial regeneration in the early stages of myocardial infarction. However, periostin participates in the progression of cardiac fibrosis, idiopathic pulmonary fibrosis and airway remodeling of asthma. In addition, we discuss the relationship between vitamin K, VKDPs and cancer, and particularly the carboxylation state of VKDPs in cancer.

1. Introduction

Scholars have explored vitamin K since it was discovered by Henrik Dam in 1935 (1). The vitamin K family belongs to the group of naphthoquinone compounds, and their common structure is composed of a 2-methyl-1,4-naphthoquinone ring and a hydrophobic polyisoprenoid side chain. Depending on the side chain length and saturation (2), vitamin K can be divided into vitamin K1 (phylloquinone, PK), vitamin K2 (menaquinones, MKs), and vitamin K3 (3). Vitamin K2 is often represented by MK-n, where n is represented for isoprene units counts, and MK comprises 15 types. The main food sources of PK are green vegetables, especially spinach, broccoli and kale. MK-4, the dominant form of MK, is found in fish, milk, liver and vegetables. Other MKs are mainly synthesized by microorganisms and are also found in Japanese natto (MK-7), cheese (MK-8, MK-9) and other food (4). Bacteria in the large intestines of humans are the main synthesizer of MKs, such as MK-7, MK-8, MK-10 and MK-11, with the exception of MK-4. MK-4 is formed by PK or vitamin K3 through in vivo tissue-specific transformation, which is also the mechanism underlying the biological activities of PK and vitamin K3 (3). The form and content of MK in different regional food supplies differs due to the food species limit. Natto is irreplaceable in the traditional Japanese diet, and cheese is a staple of dairy product supply in Europe. It is thus inevitable for MK uptake across regions to be imbalanced.

Osteoporosis is a systemic skeletal disorder with a globally high incidence that is exacerbated by the problem of an aging population. Osteoporosis has three types, which are termed primary osteoporosis, secondary osteoporosis and idiopathic osteoporosis (5). The most common type in older women is postmenopausal osteoporosis, which is a form of primary osteoporosis. Subsequent fractures, particularly hip fractures, seriously affect the survival prospects and life quality of the elderly. Based on predictions of the Asian Federation of Osteoporosis Societies, the total number of hip fractures are due to reach 2.56 million by 2050 in the studied Asian countries (6). Calcium supplements are the most well-known non-prescription therapy for strengthening bone mineral density and preventing osteoporosis. However, the calcium paradox, a consequence of damaged calcium metabolism, is identified as the loss of calcium in the bones parallel with the formation of calcification in the arteries in the elderly (7), and exists as a potential risk of calcium supplements. Evidence has accumulated that vitamin K can be of benefit in avoiding the calcium paradox. In addition, VKDPs, such as osteocalcin (OC), indicate a beneficial effect on bone strength loss.

Cardiovascular diseases (CVDs), such as acute myocardial infarction, atherosclerosis and heart failure, are the main cause of human deaths worldwide. These diseases, not only pose a great threat to patients' health, but also disturb their families and even society. An epidemiological study of 709 multiethnic adults, with follow-up at an average of 11.0 years, showed VKDP activity is associated with the incidence of ischemic cardiovascular events (8). The relationship between vascular calcification and disease has become a research focus due to the increasing rates of morbidity and mortality of CVDs. An epidemiological study of 116,309 individuals, with follow-up at an average of 28 years, indicated an aortic arch calcification exhibited a positive correlation with an increased risk of coronary heart disease (9). Moreover, another epidemiological study showed coronary artery calcium was independently associated with cardiac events (10). The matrix Gla protein (MGP), a kind of VKDP, synthesized by vascular smooth muscle cells (VSMCs) is widely expressed in soft tissues, such as cartilages and blood vessels (11), especially in calcified tissues. It has been suggested that MGP regulates vascular calcification and various important pathological processes. In fact, many emerging proteins related to vitamin K are involved in the fight against vascular calcification and are described in more detail below.

Kidney disease poses a great threat to health. According to the course duration of the disease, the disease can be classified as acute kidney disease or chronic kidney disease (CKD). Various causes have been aligned closely with CKD. To be specific, diabetes and hypertension are the two main contributing factors of CKD in developed countries. However, glomerular diseases still occupy an important position in developing countries. Sub-clinical vitamin K deficiency exists in most CKD patients, with the characteristic of low circulating vitamin K level and high inactive VKDP level (12-14). The factors that contribute to this situation include low vitamin K intake and reduction in the carboxylation process of VKDPs (15). In addition, cardiovascular complications are the main reason for the mortality of CKD patients (16). The protective effect of some VKDPs, such as MGP, on both the kidney and cardiovascular system, has been widely explored.

Numerous studies are available on OC and MGP. The aim of the current review is to focus on three emerging VKDPs that are increasingly being studied: Growth arrest-specific protein 6 (Gas6), Gla-rich protein (GRP), and periostin and their roles in various physiological and pathological processes.

2. Uptake, distribution and vitamin K cycle

Both vitamin K1 and vitamin K2 are absorbed by the small intestine and are transferred to liver in the form of chylomicrons. After absorption into the blood by liver, vitamin K1 completes the carboxylation of coagulation factors in the liver and be eliminated via circulation rapidly (17). By contrast, vitamin K2, especially long chain derivatives, are reapportioned throughout the body due to the long half-life in circulation and play vital roles in the extra-hepatic tissues (18,19).

Vitamin K is metabolised in the human body through the vitamin K cycle (20). The three forms of vitamin K in this cycle are quinone (K), vitamin K hydroquinone (KH2) and vitamin K epoxides (KO). K is initially reduced to KH2, which is oxidised into KO under the effect of epoxidase (GGCX). KO is then reduced to KH2, and vitamin K epoxide reductase (VKOR) participates in the process. After repetition of the above steps, the vitamin K cycle is formed. It is worth mentioning that Warfarin exerts anticoagulant effects to inhibit VKOR activity and induce the cellular production of a large number of nonreactive substances into the coagulation system (21). The protein containing glutamate (Glu, -CH2CH2COOH) residues in the body is also catalysed into γ-carboxyglutamate [Gla, -CH2CH(COOH)2] under the action of the key enzyme gamma-glutamyl carboxylase (GGCX) and co-actors KH2, carbon dioxide and oxygen (22). The protein containing Glu residues is known as VKDP. The Glu residues in VKDPs that can be transformed are usually located in an amino acid region known as the Gla domain. It is worth mentioning that the Gla domain formed after carboxylation of VKDP is the key to its biological function. For instance, Gla domain at the N-terminal provides a special bond for the interaction of vitamin K-dependent blood coagulation proteins with cell membranes containing phosphatidylserine, and this binding is requisite for blood coagulation (23).

3. VKDPs

At present, scholars have identified 17 types of VKDPs in humans. Seven of them are dependent on vitamin K1 to play their roles in the liver (coagulation factor II, VII, IX, X and anticoagulant proteins C, S, Z). Six of them were modified by vitamin K after transcription and were involved in various physiological and pathological processes in extrahepatic tissues. They are OC, MGP, Gas6, GRP, periostin and periostin-like-factor. The remaining four proteins need further study (proline-rich Gla protein 1, proline-rich Gla protein 2, transmembrane Gla protein 3 and transmembrane Gla protein 4) (Table I).

Table I

The 17 types of VKDPs in humans.

Table I

The 17 types of VKDPs in humans.

DesignationMain distributionGla domainFunctionRelated pathological process
Coagulation factor II (prothrombin)Liver10 Gla residuesPro-coagulant (24)Thrombosis (24)
Coagulation factor VII (proconvertin)Liver10 Gla residuesPro-coagulant (24)Thrombosis (24)
Coagulation factorIX (antihemophilic factor B)Liver10 Gla residuesPro-coagulant (24)Thrombosis, ameliorating hemophilia B (24,25)
Coagulation factorXLiver11 Gla residuesPro-coagulant (26)Thrombosis (26)
Anticoagulant protein CLiver9 Gla residuesAnticoagulant, anti-inflammatory and anti-apoptotic, cell protectant (27-29)Preventing thrombosis and stroke, resisting severe sepsis (29-31)
Anticoagulant protein SLiver11 Gla residuesAnticoagulant, anti-inflammatory, immunoregulation, regulator of apoptotic cell clearance, promoter of vasculogenesis and angiogenesis (32,33)Preventing thrombosis (34), ameliorating diabetes (35), promoting tumor metastasis (33)
Anticoagulant protein ZLiver13 Gla residuesAnticoagulantPreventing thrombosis, fetal loss and antiphospholipid syndrome (36,37)
Proline-rich Gla protein 1Spinal cordThe Gla domain exposed extracellularlySignal transduction (38)Not clear
Proline-rich Gla protein 2ThyroidThe Gla domain exposed extracellularlySignal transduction (38,39)Not clear
Transmembrane Gla protein 3Heart, brain, kidney13 Gla residuesProtein turnover, cell-cycle progression, and signal transduction (40)Warfarin embryopathy (40)
Transmembrane Gla protein 4Kidney, pancreas, placenta9 Gla residuesProtein turnover, cell-cycle progression, and signal transduction (40)Warfarin embryopathy (40)
OCBone3 Gla residuesRegulator of bone homeostasis, bone mineral density, systemic glucose and energy metabolism (41,42,43)Preventing osteoporosis, osteoarthritis (44)
MGPLung, heart, kidney5 Gla residuesInhibitor of soft tissue mineralization (45-47)Osteophyma, cardiovascular disease (43)
Gas 6Brain, heart, lung, kidney11 Gla residuesAnti-vascular calcification, regulator of cell proliferation, migration, apoptosis and senescence, and anti-inflammatory (48-52)Preventing vascular calcification, acute kidney injury, assisting tumor progression (49,50,53,54)
GRPBone, cartilage16 Gla residuesInhibitor of osteogenic differentiation, regulator of skeletal homeostasis, anti-vascular calcification, and anti-inflammatory (55-59)A dual role in osteoarthritis, preventing vascular calcification and triple-negative breast cancer (56,59-62)
PeriostinPeriosteum, periodontal ligament4 Gla residuesRegulator of periosteum activation and cardiac fibrosis, promoter of cell proliferation, differentiation, adhesion and angiogenesis (63-68)Fracture healing, cardiac fibrosis, idiopathic pulmonary fibrosis, asthma (63,68-71))
Periostin-like-factorHeart, bone, vascular smooth muscle cells4 Gla residuesPromoter of osteoblast proliferation and differentiation (64)Fracture healing, heart failure (64,72)

OC was the first VKDP to be identified that is synthesized and secreted by bones. Originally, researchers found osteocalcin has the ability to attract calcium ions. Vitamin K lowers serum undercarboxylated OC (ucOC) concentrations and increases carboxylated OC (cOC). Furthermore, cOC can bind with hydroxyapatite crystals, the material of the bone matrix, while simultaneously promoting bone mineral density (41,73). Moreover, it has been suggested during the past decade that OC shows functions of regulating systemic glucose and energy metabolism (42).

MGP plays a beneficial role in vascular calcification and various pathological processes. MGP regulates vascular calcification by eliminating the calcification effect of bone morphogenetic protein (BMP)-2 and BMP-4 (46,47). Additionally, the MGP-fetal-A complex inhibits ectopic mineralization by binding to alkaline calcium phosphate crystals (47). Based on these mechanisms, MGP is related to the prevention of cardiovascular and chronic kidney disease. In a previous review, we presented a new viewpoint, namely, that osteophyma may be caused by the accumulation of uncarboxylated MGP, in which vitamin K is required by the carboxylation process (43).

In recent years, a number of emerging VKDPs, such as Gas6, GRP, and periostin, have been considered to participate in multifarious physiological and pathological processes.

4. Gas 6

Brief introduction to Gas 6

Gas 6, weighing 75 kDa, is a relatively large member of the VKDP family. The concentration of plasma Gas 6 ranges from approximately 2.5 to 18.8 µg/l in healthy adults (74). Gas 6 is highly homologous with Protein S and carries an N-terminal Gla domain after vitamin K carboxylation. Gas 6 is widely expressed in brain, heart, lung, kidney and other tissues, with the exception of the liver (43). In 1995, Gas 6 was reported as the endogenous ligand for the TAM family for the first time (75). TAM is the acronym for three receptors: Tyro3, Axl and Mer. Among these, Axl has the highest affinity to Gas 6 (76). It has been reported that the laminin-like globular domain of Gas 6 at C-terminus appears to be the binding site of TAM receptors (75). However, after warfarin inhibits vitamin K-dependent carboxylation, inactivated Gas6, not only completely inhibits the autophosphorylation of the Axl receptor, but also fails to bind to the Axl receptor in vitro (77,78). Therefore, vitamin K-dependent carboxylation is the key to the interaction between Gas 6 and TAM receptor. In light of numerous previous studies, the binding of Gas 6 and its receptors activated downstream signaling, such as of phosphatidylinositol 3-kinase (PI3K), extracellular signal regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, to adjust the processes of apoptosis, survival, proliferation, migration and adhesion (48,79-82).

Gas 6 and the cardiovascular system

There is an inseparable relationship between Gas 6 and the cardiovascular system. The binding of Gas 6 and Axl limits the apoptosis of VSMCs by activating Akt and PI3K (80). It is worth mentioning that vitamin K2 can inhibit VSMC calcification and apoptosis by restoring Gas6 expression and activating downstream signaling by Axl, Akt and Bcl2 (49,50). Endothelial progenitor cells (EPCs) are involved in the saving response to ischemic tissue through forming new blood vessels or proliferation of pre-existing vasculature. Autologous EPC transplantation therapy has been indicated as safe and practical in chronic myocardial ischemia (51). It has been identified that Gas6 has the ability to stimulate EPC proliferation and migration in vitro by activating the Akt signaling pathway (48). The finding provides a basis for the further therapy of vascular re-endothelialization. Vascular aging, a risk factor of CVDs, is characterized by vascular stiffness, vascular remodeling and endothelial dysfunction (83). Aging vessels provide a good environment for CVDs. Gas6/Axl can delay cell cycle arrest, which is a key cause in the development of VSMC senescence and promotes their transition from the G1 to the S phase. The PI3K/Akt/Forkhead box O (FoxO) signaling pathway is considered the major target of Gas6/Axl signaling in VSMC senescence, with FoxO being the key factor (84). Furthermore, clinical investigation has demonstrated that Gas 6 plasma levels at admission reflect the existence of potential cardiovascular risks and can prognosticate cardiovascular events (52).

Accumulating evidence has indicated that Gas 6 is significantly secreted by VSMCs in human atherosclerotic plaques, but there is no secretion in healthy blood vessels. The anti-inflammatory cytokine transforming growth factor β (TGF-β) induces the secretion of Gas 6 in VSMCs, and then, stimulated by Gas 6, the VSMCs suppress the expression of inflammatory factors, such as tumor necrosis factor (TNF) α and intracellular adhesion molecule (ICAM)-1 (85). Thus, Gas 6 acts as a protective factor in human atherosclerosis. Of note, Gas6 levels inversely related to complexity and stability in patients with carotid atherosclerotic plaques (85,86). In particular, it should be noted that Gas6-deficient mice show more stable atherosclerotic lesions than normal mice, and inhibition of Gas 6 is considered to be beneficial to plaque stabilization (87). The contradictory feature between humans and mice is associated with obvious species physiological differences (88).

Of note, overexpression of Gas 6 has a detrimental effect on some pathological processes. The renin-angiotensin-aldosterone system is closely connected with cardiovascular and renal inflammation and fibrosis. It has been emphasized that Gas 6 deficiency prevents the damage of aldosterone on target organs (89). In addition, cardiomyocyte-specific Gas 6 overexpression hastens the deterioration of pathological cardiac hypertrophy, mainly due to the activation of mitogen-activated protein kinase (MAPK) kinase 1/2-ERK 1/2 signaling (90).

Gas 6 and the kidney

The contribution of Gas 6 to acute kidney injury is closely related to its biological functions, such as anti-inflammation and immunoregulation (91,92). The kidney, despite being a rich blood supplying organ, is susceptible to hypoxic injury due to the complex balance of renal blood flow, glomerular filtration rate, oxygen consumption and arteriovenous oxygen shunting (93). Previous findings suggested that Gas 6 protected against renal ischemia-reperfusion injury in a mouse model (94). To be specific, with the assistance of Gas 6 treatment, creatinine and blood urea nitrogen decreased by 29 and 27%, respectively. Cell apoptosis was significantly decreased, attributable to Gas 6 enhancing macrophages to uptake apoptotic cells (95). Furthermore, the expression of pro-inflammatory cytokines, such as interleukin (IL)-1β and TNF-α, was markedly reduced by another Gas 6 function, dampening the inflammatory responses (11,91,94). Similarly, concentration of Gas 6 rose in sepsis-induced acute kidney injury mice, and improved the survival rate by reducing serum urea nitrogen, creatinine and renal tissue apoptosis (53). In addition, several reports demonstrated that Gas6 levels were significantly increased in CKD patients and chronic hemodialysis patients (96,97). Opinions regarding the potential mechanisms vary. Researchers tend to associate the elevation with endothelial function (Gas6 is expressed by endothelial cells) and inflammation because pro-inflammatory cytokines are abundant in the blood of these patients (96,98). It is reported that endothelial cells in CKD are subjected to specific stress overtime which leads to accelerated cardiovascular disease and high mortality (99). Disruption and inflammation of glomerular capillaries influence the evolution of CKD, and, consequently, elevated Gas 6 levels (100). It is worth noting that Gas 6 is upregulated in many forms of inflammatory nephropathy, for example, lupus nephritis and IgA nephropathy (101,102).

Diabetic nephropathy is a common complication of diabetes that can further develop into end-stage renal disease. There are opposing conclusions on the tendency of plasma Gas 6 in diabetes and diabetic nephropathy. Nagai et al first reported that the expression of both Gas6 and Axl was distinctly increased in diabetic rats and proved Gas 6 can induce mesangial cell hypertrophy, which further leads to glomerular hypertrophy in the early stage of diabetic nephropathy (103). Furthermore, a reliable mechanism was proposed in which high glucose stimulates mesangial cells, followed by activating Gas6/Axl and the Akt/mTOR pathway, which results in mesangial and glomerular hypertrophy (104). By contrast, Hung et al indicated that plasma Gas6 levels in impaired glucose tolerance patients and type 2 diabetes were significantly decreased (105). A study based on individuals with different degrees of albuminuria offers some insight into this controversy, and showed the blood level of Gas 6 decreased with the deterioration of proteinuria (106). Silaghi et al formulated a hypothesis that the interaction between molecular charge and weight may participate in glomerular filtration of Gas 6 (100). More specifically, Gas 6 and albumin (approximately 66 kDa) have a similar molecular weight and a net negative charge repelled the glomerular membrane. Complex interactions eventually lead Gas 6 to filter through the glomerular membrane and be excreted from the body (100). Therefore, the concentration of plasma Gas 6 changes in different stages of diabetes.

Gas 6 and cancer

The contribution of Gas6 to cancer has been reported for a large number of cancer types. For example, Gas 6 is upregulated in breast cancer, melanoma and ovarian cancer (107-109). Tumor cells lack the competence to produce Gas 6, but can educate infiltrating macrophages to promote the production of Gas6 by producing IL-10 and macrophage colony-stimulating factor (M-CSF) (110). Previous findings have shown the pro-tumor effects of Gas6/TAM signaling. In the case of Gas 6 overexpression, the survival of myeloma cells was significantly increased in vitro and, conversely, the deficiency of Gas 6 led to rapid cell death of myeloma (111). In addition, the autocrine Gas 6 assists the resistance of myeloma cells to bortezomib (111). Recently, the pro-tumor effects of Gas 6 was also reported in lung cancer cells (54). In addition, blocking Gas 6/Mer signaling with Mer receptor inhibitors significantly limits the proliferation and growth of lung cancer cells (54). Interestingly, a high level expression of Axl and its ligand Gas 6 were recognized in non-small cell lung cancer patients, who acquired resistance with epidermal growth factor receptor tyrosine kinase inhibitors (112). It has been reported that Gas 6 negatively regulates the proliferation and interferon-γ production of natural killer cells to inhibit tumor immunity through binding with Casitas B cell lymphoma-b/TAM receptors (113). In addition, Gas 6 prolongs VSMC survival in the tumor microenvironment, which is requisite to tumor angiogenesis (79). Several investigations have indicated the roles of Gas 6 in predicting the prognostic risk of cancer. Gas 6 protein as an independent predictor always indicates a poor prognosis (107,109) (Fig. 1).

5. GRP

Brief introduction to GRP

As its name suggests, GRP, which was first identified in sturgeon cartilage, has abundant Gla residues (15 Gla residues in human) (114,115). With unusually high capacity to bind calcium through Gla resdues, GRP accumulates in bone, cartilage and ectopic calcification, such as blood vessels and skin (112). During physiological conditions, GRP participates in the stabilization of cartilage matrix, chondrogenesis and inhibition of osteogenesis (116-118). Recently, GRP has attracted attention due to its crucial performance in combating ectopic calcification.

GRP and bones

The growth of long bones is inseparable from the process of endochondral ossification. First, chondrocytes participate through a combination of proliferation, extracellular matrix secretion and hypertrophy. Then, hydroxyapatite crystals are deposited in the extracellular matrix surrounding late hypertrophic chondrocytes, known as mineralization. Next, chondrocyte death, matrix degradation and contents invasion occur. Finally, the growth plates close and the bones mature (119). Surmann-Schmitt et al reported GRP in the upper zone of the growth plate, termed unique cartilage matrix-associated protein, which exhibits a negative correlation with osteogenic differentiation (116). Both GRP knockdown zebrafish and warfarin-exposed zebrafish show irreversible growth retardation and altered skeletal development; therefore Gla residues are necessary for the function of GRP (117). It is worth mentioning that a similar feature is found in human warfarin embryopathy, which results in pregnant women from warfarin therapy (120,121). Surprisingly, GRP is not essential for mouse skeletal development (55). However, the fact that GRP is still expressed in adult mouse cartilage indicates that GRP may contribute to skeletal homeostasis and other calcification-associated pathological processes after infancy.

Osteoarthritis (OA), a painful joint disease, is characterized by articular cartilage degradation, bone remodeling, tissue inflammation and abnormal extracellular matrix mineralization. In fact, GRP plays a dual role in OA. GRP prevents articular cartilage degradation in two practical ways. On the one hand, GRP blocks the aggrecanase activity of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 by physical interaction (56,57). Aggrecanolysis is considered the main process of cartilage degradation, thus GRP protects cartilage by increasing its resistance to aggrecan cleavage in OA. By contrast, enhanced chondrocyte apoptosis accelerates the cartilage damage in OA. It is reported that chondrocyte cell death is markedly increased in GRP-deficient mice; thus, GRP protects articular cartilage by reducing chondrocyte apoptosis (56). However, GRP has also been implicated in bone remodeling, which is mediated with the altered function and metabolism of osteoblasts and osteoclasts in OA (122). Previous findings have shown osteoblasts contribute to phenotypic changes and osteoclasts are associated with cartilage destruction in OA (56,123). Additionally, GRP, as a downstream gene of runt-related transcription factor 2 and Osterix, stimulates osteoblast differentiation in OA (60). Similar results have been found in mice, in which osteoblasts and osteoclasts decreased during experimental OA in GRP-deficient mice, while there was no fluctuation in normal mice (56). The obvious conflict regarding the effect of GRP on osteoblastic differentiation may be explained by post-translational modification of GRP (56,60,116). Moreover, certain data have indicated GRP promotes osteophyte formation in OA and the effect occurs via bone remodeling rather than cartilage maturation (57,60). In addition, inflammation presents before the joint structure changes in OA joints (124). It has been demonstrated that GRP has a similar inhibitory effect on calcification and inflammation processes (58). Furthermore, synovial fluid GRP levels in OA patients exhibit a positive correlation with radiographic findings and symptomatic severity of OA (125). However, it is noteworthy that studies have shown that vitamin K deficiency is a potential risk factor for knee OA (126). Due to the lack of effective treatment and prevention methods currently, fully carboxylated GRP by vitamin K supplementation is a convenient and inexpensive candidate for the treatment of OA.

GRP and vascular calcification

Vascular calcification is a pathological process characterized by the deposition of calcium phosphate crystals in vessel walls (127,128). According to the location of calcification, it can be classified into intimal calcification (related to plaque burden and luminal narrowing) and medial calcification (associated with vessel stiffness and vascular compliance decline) (128). VSMCs are a contractile phenotype in the physiological state that can regulate vascular tension. However, they lose expression of contractility-related genes when vascular injury exists and are further transformed into osteoblast-like cells (129). In addition, bone matrix regulatory proteins, such as BMP-2, BMP-4, osteopontin, MGP and OC, are expressed in calcifying vessels (130). In response to the high level of extracellular calcium and the lack of calcification inhibitors, VSMCs release extracellular vesicles (EVs) into circulation with good mineralization capability and form a nucleation site for hydroxyapatite (131,132). Fetuin-A, a 48 kDa protein, is synthesized in the liver and secreted into circulation as a powerful calcification inhibitor. Interestingly, fetuin-A is too large to enter the collagen fibril where the mineral grows (133). It is reported that the mineral grows only inside the fibril when fetuin-A exists, whereas it grows beyond the fibril without fetuin-A (134). Therefore, fetuin-A is the key factor in determining the location of mineral growth. Moreover, inflammatory activity takes part in early calcification. Many studies have indicated a synergistic interaction between macrophage and VSMC calcification. Activated macrophages produce a large number of proteases to enhance the degradation of elastin and collagen (124,135). Macrophages markedly increased BMP-2 expression in VSMCs and also released EVs with calcification capacity (136,137). In addition, many other factors influence the process of vascular calcification, for instance, VSMC apoptosis, oxidative stress and endothelial dysfunction (138,139).

GRP, a VKDP, has been identified as a powerful inhibitor of vascular calcification. GRP, MGP and fetuin-A form a large complex that is loaded in noncalcifying EVs but distinctly lowered in high calcium-loaded vesicles, thus recommending GRP as an important mineralization inhibitor (59,61). Furthermore, calciprotein particle (CPP), a fetuin-mineral complex, principally contains mineral, fetuin-A, MGP and GRP, and contributes greatly to the stabilization of minerals. Research has demonstrated that CKD patients possess CPPs with a lower content of fetuin-A and GRP compared with healthy individuals (138). Fetuin-A is predominant in healthy CPPs and retards the deterioration toward calcifying CPPs through collaboration with GRP (140,141). Moreover, GRP shows the ability to counteract inflammation and is found in macrophage-derived EVs (142). In vitro studies found calcification in both GRP-deficient and normal VSMCs in response to osteogenic medium after 6 days, yet GRP-deficient VSMCs calcified about twice as much as normal VSMCs 9 days later (143). Of note, there is an apparent increase in the expression of BMP-2 and its downstream marker (small mother against decapentaplegic, SMAD) and, finally, after comparing GRP with two different carboxylation states, the direct interaction between the carboxylated GRP and BMP-2 was confirmed (143). Therefore, GRP disturbs the BMP-2-SMAD signaling in calcifying VSMCs, playing a central role in VSMC calcification (Fig. 2).

GRP and cancer

Microcalcification, a small deposit of calcium with a diameter less than 1 mm in mammographic images, is vital for the diagnosis and prognosis of breast cancer (61). Ductal carcinoma in situ can be as high as 20-25% in women with asymptomatic breast cancer (144). Furthermore, 70% of ductal carcinoma in situ can be diagnosed only by microcalcification in mammography (145). Recent findings have shown that linear branching microcalcifications in mammography indicate the aggressive of tumor tissue (146). A differential accumulation pattern of carboxylated GRP (cGRP) and under-carboxylated GRP (ucGRP) by vitamin K has been recently emphasized in human breast cancer (147). In healthy mammary gland tissues, cGRP was predominant, while ucGRP was found to be either co-localized or undetectable. By contrast, ucGRP was widely detected in tumor cytoplasm, while cGRP was only intermittently found in certain tumor cells. There are many explanations for the large quantity of ucGRP in tumors. It has been observed that the decreased level of vitamin K in tumor areas is in contrast to non-tumorous areas (148). Patients with tumor complications, such as venous thromboembolism, have received long-term therapy with vitamin K antagonists and the potential detrimental effects to GRP should be noted (149). In addition, prolonged subclinical vitamin K deficiency has been identified in cancer patients. Furthermore, vitamin K preferentially supports the coagulation factor synthetic process in the liver, and only after the vitamin K supply has met the liver's need is the excess vitamin K transported to extra-hepatic tissues (177,150). Thus, ucGRP is widespread in tumor tissues. Furthermore, the formation mechanism of microcalcification in breast tumor tissue is similar to physiological bone mineralization and pathological vascular mineralization (151). Both cGRP and ucGRP showed an advanced affinity to calcium mineral deposits in breast cancer tissue. Thus, with the capability of resisting ectopic calcification, GRP is considered a novel effective antagonist against cancer. It is worth noting that triple-negative breast cancer is a subtype with low expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor (62). Therefore, there is a lack of effective targeted therapy drugs for triple-negative breast cancer. However, recent research may be useful in resolving this issue. GRP inhibits the growth, migration and invasion of triple-negative breast cancer tissues in vitro and in vivo (62). Moreover, according to survival analysis in the open database, the relapse-free survival rate of patients with triple-negative breast cancer was significantly correlated with high GRP expression (62).

6. Periostin

Brief introduction to periostin

Periostin, initially known as osteoblast-specific factor 2, was first cloned from a cDNA library of the mouse osteoblastic cell line MC3T3-E1 in Japan (152). Over a decade later, the Gla-containing protein, periostin, was determined to require vitamin K-dependent carboxylation and became the 13th member of the VKDP family (153). Characterized by fasciclin domains, periostin is particularly expressed in connective tissues submitted to constant mechanical stresses (153). For example, periosteum, the periodontal ligament, heart valves and skin. Periostin has also been implicated in fibrosis, inflammation, tumor metastasis and the fracture healing process (67,154-156).

Periostin and bone

Fractures are one of the most common traumatic injuries to humans. Most fractures can be repaired to their pre-injury state through a process similar to embryonic skeletal development. According to the characteristics of fracture healing, the process is divided into four partially overlapping phases: The inflammation phase, the soft callus phase, the hard callus phase and the remodeling phase (157). The inflammation phase is marked by acute inflammation, hematoma formation and skeletal stem cell recruitment. During the soft callus phase, cartilaginous callus and nascent blood vessels form. During the hard callus phase, the most active phase of osteogenesis, the cartilage is reabsorbed and bone is deposited by osteoblasts (158). Angiogenesis also continues during this phase. During the last phase, primary bone is eventually replaced by lamellar bone, which supports normal skeletal functions, and vascular remodeling is finally completed (158,159). There is a vital association between periosteum and fracture repair. In a mouse model in which graft femoral bone was segmentally transplanted, the periosteum showed positive osteogenic and angiogenic activity, leading to superior healing and repair of live isografts (160). However, absence of the periosteum led to poor cartilaginous callus formation, and even fracture non-union (160,161). The periosteum is anatomically comprised of an outer fibrous layer and an inner cambium layer. The fibrous layer contains fibroblasts, collagen, and elastin fibers, along with a nerve and microvascular network (162). The cambium layer is directly closed to the bone surface and contains high-quality mesenchymal progenitor cells, osteoblasts, fibroblasts, microvessels and sympathetic nerves (162,163). In human bones, periostin is highly expressed in the cambium layer, where it is highly active during bone remodeling (164). In a mouse model of fracture, rapid periostin gene expression occurred during the inchoate phase of fracture healing (155). In the first 1-2 weeks after fracture, human serum periostin is decreased initially, prior to a progressive elevation that peaks at 8 weeks, and is present for about 26 weeks (165).

Periostin participates in almost all phases of fracture healing. In the early inflammation phase, as a result of the inflammatory response or paracrine effects of the periosteum, periostin is present at a low level in serum (165). Transplantation of the periosteum of periostin-deficient mice to the fracture site of wild-type mice induced negative fracture repair, indicating that periostin regulates periosteum activation (66). Skeletal stem cells (SSCs), with local osteogenic potential, are recruited in the early stage of bone regeneration and periosteum and is considered one of its major sources (166). As an extracellular matrix protein, periostin promotes the migration of SSCs by binding integrin receptors on the cell surface (162,167). Notably, periosteal cells, another form of convened cells that shares a common embryonic origin with SSCs, have been revealed to have greater regenerative potential than SSCs (63). Moreover, periosteal cell functions are impaired in mice lacking periostin, suggesting that periostin contributes to periosteal cell activation (63). During the callus phases, induced by BMP-2, periostin is upregulated in soft callus and osteoblasts (168). Accumulating evidence has indicated that abundant periostin facilitates the proliferation, differentiation and adhesion of osteoblasts in bone formation (64,65). In addition, periostin may interfere with osteoclasts in a similar way (65). It is reported that periostin markedly increases arterioles in a calvarial defects model, proving periostin promotes angiogenesis (66). Periostin has a crucial mission in the last phase of fracture healing, that is, to recover the periosteum niche of periosteal cells. In a periosteum transplantation model, periosteal cells may still be re-activated to contribute to cartilage within the callus after three injury cycles (63). By contrast, when periostin-deficient grafts were transplanted into wild-type hosts, the contribution of periosteal cells to repairing of the second fracture injury disappeared, leading to defective callus formation and fibrosis, and furthermore this was not due to deficient proliferation (63). Therefore, periostin plays a crucial role in maintaining periosteal cell niche and supporting bone remodeling.

Long-term anticoagulant therapy with vitamin K antagonists, such as warfarin, reduces bone density and increases the risk of osteoporosis (169,170). Previous findings have shown that warfarin significantly inhibits osteoblastic differentiation (171). Warfarin interferes in the carboxylation of periostin by antagonizing the function of vitamin K, and the decrease of carboxylated periostin is one of the main causes of bone density reduction (172). By contrast, vitamin K2 promotes mineralization of osteoblasts (173). In recent years, periostin has been recommended as a potential predictive marker of bone events. Osteoporotic fracture is a major cause of disability in the elderly, while the ability of current predicting methods is limited. In a cohort of 607 postmenopausal women from France that were followed up for 7 years, a positive correlation between serum periostin and fracture risk was observed (174). Furthermore, the association was independent of bone mineral density and prior fractures, indicating that periostin is an independent predictive marker of fracture risk. This hypothesis was confirmed in another case control study of Korean postmenopausal women (175). Interestingly, high plasma periostin levels prefer non-vertebral fractures to vertebral fractures, such as limb fractures (175). These clinical outcomes seem contrary to the popular view of periostin. The specific mechanisms for these conclusions need further study as they may be related to the carboxylation state of periostin or to the distribution of periostin in the body. Specifically, periostin in bone are induced to circulation. Notably, it has been demonstrated that lower serum periostin concentrations were related to prevalence of knee OA in women (176). This provides a new idea for the application of periostin in bone event prediction.

Periostin and heart

During embryogenesis, periostin supports normal valve leaflet morphogenesis and cardiac skeleton maturity (177). Periostin is implicated in CVDs, such as myocardial infarction, atherosclerosis and cardiac fibrosis-related diseases (67). Cardiac fibrosis is a prominent feature of cardiac remodeling that can further lead to heart failure and impaired cardiac function. Fibroblasts, the most abundant cell population in the heart except cardiomyocytes, rapidly differentiate into myofibroblasts in the cardiac fibrosis process (67). Abundant differentiated myofibroblasts found in hearts suffering failure also support the transformation (179). Emerging evidence suggests that the myofibroblast phenotype still has latent reversibility in end-stage heart failure (67,178). Of note, periostin, as the most specific product, is expressed in essentially all myofibroblasts (67,68). Certain data have indicated targeted ablated periostin-expressing myofibroblasts led to a diminished fibrotic area and improved the ejection fraction in hearts in AngII-induced fibrosis mice (68). In addition, not only was cardiac fibrosis reduced, but treatment also did not affect scar stability in myocardial infarction mice (68). Moreover, periostin antibody treatment visibly restricted cell viability of myofibroblasts in vitro (69). Therefore, periostin is a novel central factor contributing to the function of myofibroblasts during cardiac fibrosis. Research has demonstrated that ginsenoside Rb1, the bioactive component of ginseng, reduced the expression levels of periostin and protected rats against myocardial fibrosis (179).

According to whether exons 17 and 21 exist or not, periostin can be divided into four isoforms, i.e., Pn-1 to Pn-4. In detail, Pn-1 is a full-length form, Pn-2 is short of exon 17, Pn-3 is short of exon 21, and Pn-4 is short of exons 17 and 21 (69). Using an antibody that specifically inhibits exon 17, the dispute regarding the functions of different periostin isoforms has been settled. It is not surprising that the expression of periostin increased in the border zone on day 5 after myocardial infarction (69). However, total infarction and fibrosis size were notably reduced in an adult mouse model by selectively neutralizing an antibody against exon 17 (69). In addition, cardiac dysfunctions were improved. Moreover, Pn-2 contributes to angiogenesis in in vitro experiments, while Pn-1 does not (69). Low expression of TGF-β, a fibrosis-related gene, was associated with the inhibition of fibrosis. Thus, Pn-1 contributes to fibrosis and heart remodeling after myocardial infarction, and there is potential to improve the prognosis of myocardial infarction via selectively inhibited Pn-1 treatment. Nevertheless, neonatal mice were capable of regenerating myocardium after myocardial infarction. On day 21 after myocardial infarction, the infarcted areas of neonatal mice almost disappeared (180). However, myocardial regeneration was inhibited in periostin-deficient neonatal mice, presenting with a larger infarcted area, which was attributed to the inhibition of PI3K/glycogen synthase kinase 3β/cyclin D1 signaling pathway (180). Therefore, periostin is pivotal for myocardial regeneration at the early stage of myocardial infarction, and is involved in fibrillogenesis and scar generation in the later chronic stage.

Previous findings have shown that periostin is abundantly expressed in patients with atherosclerosis (181-183). In the 'Pathobiological Determinants of Atherosclerosis in Youth' study, the variant encoding periostin gene was connected with atherosclerotic lesion traits (181). Matrix metalloproteinases, enzymes implicated in atherosclerosis and vascular remodeling, which were induced by periostin, led to valve thickening in mice fed high-fat diets (182). Additionally, periostin stimulates angiogenesis both in vitro and ex vivo (179). In response to injury, periostin was markedly upregulated in neointimal SMCs and adventitial myofibroblasts, and promoted cell migration (183). By contrast, the plaques of periostin-deleted mice, not only had a smaller necrotic core and fibrous cap, but also possessed more cholesterol clefts (184). The deficiency of periostin also reduced the infiltration of macrophages into the plaque (184). Thus, periostin plays a considerable role in atherosclerosis, and targeted periostin treatment may delay progression of diseases associated with atherosclerosis (Fig. 3).

Figure 3

Functional mechanisms of periostin. The '+; refers to promotion. Green represents periostin physiological effects and red represents pathological effects. Periostin is particularly expressed in connective tissues, such as the periodontal ligament, periosteum and heart valves. Vitamin K and GGCX are two vital enzymes in the carboxylation of periostin. According to whether exons 17 and 21 exist or not, periostin can be divided into four isoforms: Pn-1, Pn-2, Pn-3 and Pn-4. Periostin is involved in all phases of fracture healing. Periostin promotes periosteum activation in the early stage. Subsequently, periostin facilitates the migration of SSCs via binding integrin receptors. Periostin contributes to the activation of periosteal cells, revealing greater regenerative potential than SSCs. Periostin facilitates the proliferation, differentiation and adhesion of osteoblasts and osteoclasts in bone formation. Periostin accelerates angiogenesis and maintains periosteal cell niche in the later period of fracture healing. At the embryonic stage of the heart, periostin supports heart valve development and cardiac skeleton maturity. However, periostin participates in progression of cardiac fibrosis, idiopathic pulmonary fibrosis (IPF) and asthma airway remodeling. Expressed in essentially all myofibroblasts, periostin is a central factor contributing to the function of myofibroblasts. Periostin activates fibroblasts to produce type I collagen via β1 integrin in IPF. Moreover, periostin induces epithelial-mesenchymal transformation, which leads to alveolar epithelial cells taking on the characteristics of mesenchymal cells and accelerates the aggravation of fibrosis.

Periostin and the respiratory system

In the last decade, the role of periostin in airway development and diseases has been widely emphasized. For instance, periostin was reduced in tracheal aspirate fluid of bronchopulmonary dysplasia during the window period (185). Then, TGF-β upregulated the expression of periostin in the interstitial fibrosis region (185,186). Thus, periostin is recognized as a potential biomarker that predicts the risk of bronchopulmonary dysplasia and the need for preventative therapies in preterm infants. Periostin has been involved in many respiratory disorders, such as idiopathic pulmonary fibrosis (IPF), asthma, chronic rhinosinusitis, idiopathic eosinophilic pneumonia and allergic bronchopulmonary aspergillosis (156,187-190). The most notable of these are IPF and asthma.

IPF, a common pulmonary fibrotic conditions, is a chronic progressive parenchymal lung disease of unclear cause that is limited to the lungs (191,192). Patients are predominantly older individuals and typically have progressive worsening lung function, leading to a grave prognosis (193). It has been indicated that periostin was elevated in IPF patients' circulation (190). Furthermore, more periostin was found in the lungs of IPF patients and concentrated in areas of active fibrosis (187). Interestingly, the exon 21 of the periostin gene is more likely to be spliced out in IPF lung samples than in the control (194). Injury factors activate alveolar epithelial cells disrupting the homeostatic balance between epithelial and mesenchymal cells, thus fibrotic response is driven. As an extracellular matrix protein, periostin and TGF-β regulate each other in fibroblasts (195); specifically, TGF-β increases the expression of periostin. In return, periostin significantly upregulates the production of TGF-β in fibroblasts and increases type I collagen production (70,195). However, periostin activates fibroblasts to produce type I collagen via β1 integrin, rather than the TGF-β signal (195). Similar to heart fibrosis, periostin promotes differentiation of fibroblasts to myofibroblasts. By mediating epithelial-mesenchymal transformation, periostin induces alveolar epithelial cells to take on the characteristics of mesenchymal cells, which leads to the aggravation of fibrosis (70). Emerging evidence suggests that periostin silencing drives the fibroblasts into G1 arrest of the cell cycle and retards the proliferation in IPF (196). Thus, periostin plays a pivotal role in lung fibroblast proliferation. Currently, early lung transplantation is a beneficial therapeutic option for IPF patients, and another two available drugs (Pirfenidone and Nintedanib) are able to limit IPF progress (197). Recently, a compound known as CP4715 was found to prohibit the interaction between TGF-β and periostin (197). CP4715, not only lessened bleomycin-induced pulmonary fibrosis, but also disturbed TGF-β signals in fibroblasts from IPF (195). Therefore, CP4715 may become a latent drug therapy to provide more therapeutic possibilities for IPF. It is worth mentioning that vitamin K antagonists are related to the rising mortality of IPF (198). The carboxylation status of periostin in IPF patients deserves further study. Some scholars have proposed that the use of vitamin K instead of vitamin K antagonists may help reduce the progression of IPF, but this idea needs further verification (198).

Asthma, as a heterogeneous disease, has been defined as several phenotypes according to different clinical features and physiological indexes. Nevertheless, type-2 airway inflammation is one of the main causes of asthma, which is supported by activity of type 2 cytokines, such as IL-4 and IL-13. As a result of chronic airflow limitation, airway remodeling develops in chronic severe asthma. Many studies have shown periostin is deeply involved in the process of asthma, from airway inflammation to remodeling. The periostin gene is highly induced in asthmatic airway epithelial cells with a 4.4-fold increase compared to healthy controls (199). In a cohort of asthmatics from Sweden, a negative correlation between serum periostin and lung function was observed (71). Type-2 inflammation attracts large numbers of immune cells to release cytokines, such as IL-4, IL-13 and TGF-β. These cytokines stimulate the production of periostin from fibroblasts, epithelial cells and endothelial cells, which are known as the main sources of periostin in asthma (200), and some researchers have hypothesized that eosinophils also secrete periostin (201). As an integrin ligand, periostin binds to integrin αMβ2 and α4β1 on eosinophil, guiding recruitment of eosinophils and increasing eosinophil adhesion to fibronectin (156,202). In addition, through its fibrogenic function, periostin participates in the process of subepithelial fibrosis, which is feature of airway remodeling in asthma (185). Periostin, secreted from airway epithelial cells, activates TGF-β and upregulates type I collagen via autocrine effects (70,203). Similarly, periostin activates TGF-β-mediated fibroblasts to increase the production of type I collagen (70,203). Clinical studies from Japan have reported that vitamin K2 therapy has an effective rate of up to 90.9% in patients with mild asthma (204). The effective rate was 86.7 and 72.7% in moderate and severe patients, respectively (204). In addition, vitamin K2 has a powerful ability to inhibit the release of inflammatory cytokines (205). It has also been shown that vitamin D, also a fat-soluble vitamin, can regulate inflammatory chemokines in asthma and significantly inhibit airway smooth muscle cell proliferation (205). Therefore, whether vitamin K2 can regulate the release of inflammatory factors in asthma and thus inhibit the production of large amounts of periostin remains to be further studied. Additionally, periostin increases gel elasticity formed by type 1 collagen, thus mediating the biomechanical capabilities of the airway and leading to airway remodeling (206). Accumulated evidence has indicated that high serum periostin concentrations were implicated in certain characteristics of asthma. It is reported that serum periostin concentrations were not combined with atopic status or treatment status of asthma, while high level serum periostin was related to older patients at the onset of asthma, aspirin intolerance or nasal disorders (207-209). As serum biomarkers are more convenient than lung function tests in some special cases of asthma, periostin has become one of the practical biomarkers of asthma. For instance, periostin rises significantly in severe asthma and acute asthma exacerbation of children, which is an important serum biomarker in assessing the severity of asthma (206). Of note, periostin is a helpful biomarker to detect long-term bronchial obstruction in severe asthmatic patients, as well as the sensitivity of sputum periostin beyond the serum periostin (210).

7. Discussion

In recent years, numerous physiological benefits of vitamin K2 have been identified, such as anti-vascular calcification, glycemic control and lipid-lowering effects (49,211). In general, the mechanisms by which vitamin K2 has been found to exhibit functional pluripotency can be summarized as follows. First of all, vitamin K-dependent proteins (VKDPs) regulated by vitamin K play important roles in various biological processes. In addition, vitamin K2 is a powerful antioxidant. The antioxidant activity of vitamin KH2 far exceeds that of known free radical scavengers such as alpha-tocopheroland ubiquinone (212). Vitamin K2, not only increased the number of surviving oxidative stress cells, but can also limit the amount of reactive oxygen species in cells (213). Moreover, vitamin K2 is effective in protecting mitochondrial function. Previous findings have shown that vitamin K2 can be used to substitute for ubiquinone to produce enough ATP to maintain mitochondrial function during electron transfer (214). In addition, vitamin K2 exerts anti-inflammatory activity to inflammation-stimulated cells and can inhibit the expression of inflammatory cytokines (e.g., TNF-α, IL-6 and IL-8) (215). Finally, vitamin K2 is involved in immune regulation. Specifically, T-cell proliferation was inhibited with vitamin K2 instead of vitamin K1 (216).

In this review, we highlighted three emerging VKDPs (Gas 6, GRP and periostin) that need vitamin K to conduct carboxylation and then perform various biological functions in the human body, such as bone homeostasis, heart development and anti-vascular calcification. In combination with previous studies, we believe that a high intake of vitamin K, especially vitamin K2, is beneficial for the cardiovascular system and bones. However, some questions about the relationship between vitamin K and cancer remain unsolved. Many studies have shown vitamin K2 has anticancer effects. Ishizuka et al reported that vitamin K2 has a moderately suppressive effect on hepatocellular carcinoma recurrence (217). Zhong et al indicated that vitamin K2 reduces the hepatocellular carcinoma recurrence rate after 1 year (218). Similarly, vitamin K2 exerts anti-cancer effects in cancer cell lines, such as cholangiocellular carcinoma, ovarian cancer and pancreatic cancer (219-221). Accumulating evidence has indicated that vitamin K2 not only inhibits the proliferation and differentiation of tumor cells, but also induces the apoptosis and autophagy of tumor cells (222). In addition, however, some VKDPs represented by Gas6 have been indicated to facilitate the survival and metastasis of cancer cells. Moreover, as mentioned above, GRP carboxylation status in breast cancer tissues is significantly different from those in normal tissues, but there are few studies measuring this in other diseases. Thus, the relationship between measurement of VKDP carboxylation status and disease progression remains to be further investigated. Furthermore, periostin is a newly identified VKDP that has been extensively studied in the heart and respiratory system. However, the role of periostin as a VKDP has been rarely studied. A large number of studies have shown that the Gla domain after vitamin K carboxylation is an important structure for VKDPs to play a role; thus, this review provides a new idea for the further exploration of periostin. Overall, the process of γ-carboxylation modification has a significant effect on biological functions, although the functional results of γ-carboxylation for these proteins are not yet clear. These three emerging proteins act in different directions, so their specific roles with vitamin K2 need further study.

In conclusion, Gas6, GRP and periostin are involved in a variety of physiological and pathological processes in the body. Vitamin K is essential for their function, and thus may be a potential preventive and therapeutic agent for many diseases. Additionally, VKDPs are expected to be biomarkers for many diseases.


This study was funded by the National Nature Science Foundation of China (grant no. 30971065), the Science and Technology Plan of Dalian (grant no. 2012E12SF074) and the Education Fund Item of Liaoning province (grant no. 2009 A 194).

Availability of data and materials

Not applicable.

Authors' contributions

SL supervised the writing of the present review as well as directing its structure, and provided the final approval of the version to be published. HX designed the concept of the review and its structure, wrote and revised the manuscript. JC and LD were involved in the writing of the review. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.


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Dam H: The antihaemorrhagic vitamin of the chick. Biochem J. 29:1273–1285. 1935. View Article : Google Scholar : PubMed/NCBI


Palmer CR, Blekkenhorst LC, Lewis JR, Ward NC, Schultz CJ, Hodgson JM, Croft KD and Sim M: Quantifying dietary vitamin K and its link to cardiovascular health: A narrative review. Food Funct. 11:2826–2837. 2020. View Article : Google Scholar : PubMed/NCBI


Hirota Y, Tsugawa N, Nakagawa K, Suhara Y, Tanaka K, Uchino Y, Takeuchi A, Sawada N, Kamao M, Wada A, et al: Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J Biol Chem. 288:33071–33080. 2013. View Article : Google Scholar : PubMed/NCBI


Simes DC, Viegas CSB, Araújo N and Marreiros C: Vitamin K as a diet supplement with impact in human health: Current evidence in age-related diseases. Nutrients. 12:1382020. View Article : Google Scholar :


Mirza F and Canalis E: Management of endocrine disease: Secondary osteoporosis: Pathophysiology and management. Eur J Endocrinol. 173:R131–R151. 2015. View Article : Google Scholar : PubMed/NCBI


Cheung CL, Ang SB, Chadha M, Chow ES, Chung YS, Hew FL, Jaisamrarn U, Ng H, Takeuchi Y, Wu CH, et al: An updated hip fracture projection in Asia: The Asian federation of osteoporosis societies study. Osteoporos Sarcopenia. 4:16–21. 2018. View Article : Google Scholar


Wasilewski GB, Vervloet MG and Schurgers LJ: The bone-vasculature axis: Calcium supplementation and the role of vitamin K. Front Cardiovasc Med. 6:62019. View Article : Google Scholar : PubMed/NCBI


Danziger J, Young RL, Shea MK, Tracy RP, Ix JH, Jenny NS and Mukamal KJ: Vitamin K-dependent protein activity and incident ischemic cardiovascular disease: The multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 36:1037–1042. 2016. View Article : Google Scholar : PubMed/NCBI


Iribarren C, Sidney S, Sternfeld B and Browner WS: Calcification of the aortic arch: Risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA. 283:2810–2815. 2000. View Article : Google Scholar : PubMed/NCBI


Kondos GT, Hoff JA, Sevrukov A, Daviglus ML, Garside DB, Devries SS, Chomka EV and Liu K: Electron-beam tomography coronary artery calcium and cardiac events: A 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults. Circulation. 107:2571–2576. 2003. View Article : Google Scholar : PubMed/NCBI


Ferland G: The discovery of vitamin K and its clinical applications. Ann Nutr Metab. 61:213–218. 2012. View Article : Google Scholar : PubMed/NCBI


Cheung CL, Sahni S, Cheung BM, Sing CW and Wong IC: Vitamin K intake and mortality in people with chronic kidney disease from NHANES III. Clin Nutr. 34:235–240. 2015. View Article : Google Scholar


Fusaro M, Plebani M, Iervasi G and Gallieni M: Vitamin K deficiency in chronic kidney disease: Evidence is building up. Am J Nephrol. 45:1–3. 2017. View Article : Google Scholar


Turner ME, Adams MA and Holden RM: The vitamin K metabolome in chronic kidney disease. Nutrients. 10:10762018. View Article : Google Scholar :


Kaesler N, Magdeleyns E, Herfs M, Schettgen T, Brandenburg V, Fliser D, Vermeer C, Floege J, Schlieper G and Krüger T: Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation. Kidney Int. 86:286–293. 2014. View Article : Google Scholar : PubMed/NCBI


Di Lullo L, House A, Gorini A, Santoboni A, Russo D and Ronco C: Chronic kidney disease and cardiovascular complications. Heart Fail Rev. 20:259–272. 2015. View Article : Google Scholar


Shearer MJ, Mallinson CN, Webster GR and Barkhan P: Clearance from plasma and excretion in urine, faeces and bile of an intravenous dose of tritiated vitamin K 1 in man. Br J Haematol. 22:579–588. 1972. View Article : Google Scholar : PubMed/NCBI


Schurgers LJ, Teunissen KJF, Hamulyák K, Knapen MH, Vik H and Vermeer C: Vitamin K-containing dietary supplements: Comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 109:3279–3283. 2007. View Article : Google Scholar


Halder M, Petsophonsakul P, Akbulut AC, Pavlic A, Bohan F, Anderson E, Maresz K, Kramann R and Schurgers L: Vitamin K: Double bonds beyond coagulation insights into differences between vitamin K1 and K2 in health and disease. Int J Mol Sci. 20:8962019. View Article : Google Scholar :


Willems BAG, Vermeer C, Reutelingsperger CP and Schurgers LJ: The realm of vitamin K dependent proteins: Shifting from coagulation toward calcification. Mol Nutr Food Res. 58:1620–1635. 2014. View Article : Google Scholar : PubMed/NCBI


Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, et al: Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 141(2 Suppl): e419S–e496S. 2012. View Article : Google Scholar : PubMed/NCBI


Tie JK and Stafford DW: Structural and functional insights into enzymes of the vitamin K cycle. J Thromb Haemost. 14:236–247. 2016. View Article : Google Scholar :


Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B and Furie BC: Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struct Biol. 10:751–756. 2003. View Article : Google Scholar : PubMed/NCBI


Girolami A, Ferrari S, Cosi E, Santarossa C and Randi ML: Vitamin K-dependent coagulation factors that may be responsible for both bleeding and thrombosis (FII, FVII, and FIX). Clin Appl Thromb Hemost. 24(9 Suppl): 42S–47S. 2018. View Article : Google Scholar : PubMed/NCBI


Mahdi AJ, Obaji SG and Collins PW: Role of enhanced half-life factor VIII and IX in the treatment of haemophilia. Br J Haematol. 169:768–776. 2015. View Article : Google Scholar : PubMed/NCBI


Muller MP, Wang Y, Morrissey JH and Tajkhorshid E: Lipid specificity of the membrane binding domain of coagulation factor X. J Thromb Haemost. 15:2005–2016. 2017. View Article : Google Scholar : PubMed/NCBI


Rezaie AR: Regulation of the protein C anticoagulant and antiinflammatory pathways. Curr Med Chem. 17:2059–2069. 2010. View Article : Google Scholar : PubMed/NCBI


Mosnier LO, Zlokovic BV and Griffin JH: The cytoprotective protein C pathway. Blood. 109:3161–3172. 2007. View Article : Google Scholar


Mosnier LO and Griffin JH: Protein C anticoagulant activity in relation to anti-inflammatory and anti-apoptotic activities. Front Biosci. 11:2381–2399. 2006. View Article : Google Scholar : PubMed/NCBI


Majid Z, Tahir F, Ahmed J, Bin Arif T and Haq A: Protein C deficiency as a risk factor for stroke in young adults: A review. Cureus. 12:e74722020.PubMed/NCBI


Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 344:699–709. 2001. View Article : Google Scholar : PubMed/NCBI


Dahlbäck B: Vitamin K-dependent protein S: Beyond the protein C pathway. Semin Thromb Hemost. 44:176–184. 2018. View Article : Google Scholar


Suleiman L, Négrier C and Boukerche H: Protein S: A multi-functional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer. Crit Rev Oncol Hematol. 88:637–654. 2013. View Article : Google Scholar : PubMed/NCBI


Fricke DR, Chatterjee S and Majumder R: Protein S in preventing thrombosis. Aging (Albany NY). 11:847–848. 2019. View Article : Google Scholar


Yasuma T, Yano Y, D'Alessandro-Gabazza CN, Toda M, Gil-Bernabe P, Kobayashi T, Nishihama K, Hinneh JA, Mifuji-Moroka R, Roeen Z, et al: Amelioration of diabetes by protein S. Diabetes. 65:1940–1951. 2016. View Article : Google Scholar : PubMed/NCBI


Topalidou M, Effraimidou S, Farmakiotis D, Papadakis E, Papaioannou G, Korantzis I and Garipidou V: Low protein Z levels, but not the intron F G79A polymorphism, are associated with unexplained pregnancy loss. Thromb Res. 124:24–27. 2009. View Article : Google Scholar


Ghozlan MF, Mohamed AAE, Eissa DS and Eldawy HS: Low protein Z level: A thrombophilic risk biomarker for acute coronary syndrome. Indian J Hematol Blood Transfus. 35:339–346. 2019. View Article : Google Scholar : PubMed/NCBI


Kulman JD, Harris JE, Haldeman BA and Davie EW: Primary structure and tissue distribution of two novel proline-rich gamma-carboxyglutamic acid proteins. Proc Natl Acad Sci USA. 94:9058–9062. 1997. View Article : Google Scholar : PubMed/NCBI


Kulman JD, Harris JE, Xie L and Davie EW: Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein. Proc Natl Acad Sci USA. 104:8767–8772. 2007. View Article : Google Scholar : PubMed/NCBI


Kulman JD, Harris JE, Xie L and Davie EW: Identification of two novel transmembrane gamma-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues. Proc Natl Acad Sci USA. 98:1370–1375. 2001. View Article : Google Scholar : PubMed/NCBI


Iwamoto J: Vitamin K2 therapy for postmenopausal osteoporosis. Nutrients. 6:1971–1980. 2014. View Article : Google Scholar : PubMed/NCBI


Mizokami A, Kawakubo-Yasukochi T and Hirata M: Osteocalcin and its endocrine functions. Biochem Pharmacol. 132:1–8. 2017. View Article : Google Scholar : PubMed/NCBI


Wen L, Chen J, Duan L and Li S: Vitamin K-dependent proteins involved in bone and cardiovascular health (Review). Mol Med Rep. 18:3–15. 2018.PubMed/NCBI


Naito K, Watari T, Obayashi O, Katsube S, Nagaoka I and Kaneko K: Relationship between serum undercarboxylated osteocalcin and hyaluronan levels in patients with bilateral knee osteoarthritis. Int J Mol Med. 29:756–760. 2012.PubMed/NCBI


Sweatt A, Sane DC, Hutson SM and Wallin R: Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost. 1:178–185. 2003. View Article : Google Scholar : PubMed/NCBI


Yao Y, Zebboudj AF, Shao E, Perez M and Boström K: Regulation of bone morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells involves activin-like kinase receptor 1. J Biol Chem. 281:33921–33930. 2006. View Article : Google Scholar : PubMed/NCBI


Roy ME and Nishimoto SK: Matrix Gla protein binding to hydroxyapatite is dependent on the ionic environment: Calcium enhances binding affinity but phosphate and magnesium decrease affinity. Bone. 31:296–302. 2002. View Article : Google Scholar : PubMed/NCBI


Zuo PY, Chen XL, Lei YH, Liu CY and Liu YW: Growth arrest-specific gene 6 protein promotes the proliferation and migration of endothelial progenitor cells through the PI3K/AKT signaling pathway. Int J Mol Med. 34:299–306. 2014. View Article : Google Scholar : PubMed/NCBI


Qiu C, Zheng H, Tao H, Yu W, Jiang X, Li A, Jin H, Lv A and Li H: Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway. Mol Cell Biochem. 433:149–159. 2017. View Article : Google Scholar : PubMed/NCBI


Jiang X, Tao H, Qiu C, Ma X, Li S, Guo X, Lv A and Li H: Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. Eur J Pharmacol. 786:10–18. 2016. View Article : Google Scholar : PubMed/NCBI


Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, Uchida S, Masuo O, Iwaguro H, Ma H, et al: Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation. 107:461–468. 2003. View Article : Google Scholar : PubMed/NCBI


Jiang L, Liu CY, Yang QF, Wang P and Zhang W: Plasma level of growth arrest-specific 6 (GAS6) protein and genetic variations in the GAS6 gene in patients with acute coronary syndrome. Am J Clin Pathol. 131:738–743. 2009. View Article : Google Scholar : PubMed/NCBI


Chen LW, Chen W, Hu ZQ, Bian JL, Ying L, Hong GL, Qiu QM, Zhao GJ and Lu ZQ: Protective effects of growth arrest-specific protein 6 (Gas6) on sepsis-induced acute kidney injury. Inflammation. 39:575–582. 2016. View Article : Google Scholar


Novitskiy SV, Zaynagetdinov R, Vasiukov G, Gutor S, Han W, Serezani A, Matafonov A, Gleaves LA, Sherrill TP, Polosukhin VV and Blackwell TS: Gas6/MerTK signaling is negatively regulated by NF-κB and supports lung carcinogenesis. Oncotarget. 10:7031–7042. 2019. View Article : Google Scholar


Eitzinger N, Surmann-Schmitt C, Bösl M, Schett G, Engelke K, Hess A, von der Mark K and Stock M: Ucma is not necessary for normal development of the mouse skeleton. Bone. 50:670–680. 2012. View Article : Google Scholar


Stock M, Menges S, Eitzinger N, Geßlein M, Botschner R, Wormser L, Distler A, Schlötzer-Schrehardt U, Dietel K, Distler J, et al: A dual role of upper zone of growth plate and cartilage matrix-associated protein in human and mouse osteoarthritic cartilage: Inhibition of aggrecanases and promotion of bone turnover. Arthritis Rheumatol. 69:1233–1245. 2017. View Article : Google Scholar : PubMed/NCBI


Seuffert F, Weidner D, Baum W, Schett G and Stock M: Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis. Arthritis Res Ther. 20:882018. View Article : Google Scholar : PubMed/NCBI


Cavaco S, Viegas CS, Rafael MS, Ramos A, Magalhães J, Blanco FJ, Vermeer C and Simes DC: Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis. Cell Mol Life Sci. 73:1051–1065. 2016. View Article : Google Scholar


Viegas CS, Cavaco S, Neves PL, Ferreira A, João A, Williamson MK, Price PA, Cancela ML and Simes DC: Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications. Am J Pathol. 175:2288–2298. 2009. View Article : Google Scholar : PubMed/NCBI


Lee YJ, Park SY, Lee SJ, Boo YC, Choi JY and Kim JE: Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation. Osteoarthritis Cartilage. 23:1421–1431. 2015. View Article : Google Scholar : PubMed/NCBI


O'Grady S and Morgan MP: Microcalcifications in breast cancer: From pathophysiology to diagnosis and prognosis. Biochim Biophys Acta Rev Cancer. 1869:310–320. 2018. View Article : Google Scholar : PubMed/NCBI


Lee SH, Lee YJ, Park SI and Kim JE: Unique cartilage matrix-associated protein inhibits the migratory and invasive potential of triple-negative breast cancer. Biochem Biophys Res Commun. 530:680–685. 2020. View Article : Google Scholar : PubMed/NCBI


Duchamp de Lageneste O, Julien A, Abou-Khalil R, Frangi G, Carvalho C, Cagnard N, Cordier C, Conway SJ and Colnot C: Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin. Nat Commun. 9:7732018. View Article : Google Scholar : PubMed/NCBI


Zhu S, Barbe MF, Liu C, Hadjiargyrou M, Popoff SN, Rani S, Safadi FF and Litvin J: Periostin-like-factor in osteogenesis. J Cell Physiol. 218:584–592. 2009. View Article : Google Scholar


Cobo T, Viloria CG, Solares L, Fontanil T, González-Chamorro E, De Carlos F, Cobo J, Cal S and Obaya AJ: Role of periostin in adhesion and migration of bone remodeling cells. PLoS One. 11:e01478372016. View Article : Google Scholar : PubMed/NCBI


Heo SC, Shin WC, Lee MJ, Kim BR, Jang IH, Choi EJ, Lee JS and Kim JH: Periostin accelerates bone healing mediated by human mesenchymal stem cell-embedded hydroxyapatite/tricalcium phosphate scaffold. PLoS One. 10:e01166982015. View Article : Google Scholar : PubMed/NCBI


Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, Brody MJ, J Lin SC, Aronow BJ and Tallquist MD: Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun. 7:122602016. View Article : Google Scholar : PubMed/NCBI


Kaur H, Takefuji M, Ngai CY, Carvalho J, Bayer J, Wietelmann A, Poetsch A, Hoelper S, Conway SJ, Möllmann H, et al: Targeted ablation of periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ Res. 118:1906–1917. 2016. View Article : Google Scholar : PubMed/NCBI


Taniyama Y, Katsuragi N, Sanada F, Azuma J, Iekushi K, Koibuchi N, Okayama K, Ikeda-Iwabu Y, Muratsu J, Otsu R, et al: Selective blockade of periostin exon 17 preserves cardiac performance in acute myocardial infarction. Hypertension. 67:356–361. 2016. View Article : Google Scholar


Izuhara K, Conway SJ, Moore BB, Matsumoto H, Holweg CT, Matthews JG and Arron JR: Roles of periostin in respiratory disorders. Am J Respir Crit Care Med. 193:949–956. 2016. View Article : Google Scholar : PubMed/NCBI


James A, Janson C, Malinovschi A, Holweg C, Alving K, Ono J, Ohta S, Ek A, Middelveld R, Dahlén B, et al: Serum periostin relates to type-2 inflammation and lung function in asthma: Data from the large population-based cohort Swedish GA(2)LEN. Allergy. 72:1753–1760. 2017. View Article : Google Scholar : PubMed/NCBI


Litvin J, Blagg A, Mu A, Matiwala S, Montgomery M, Berretta R, Houser S and Margulies K: Periostin and periostin-like factor in the human heart: Possible therapeutic targets. Cardiovasc Pathol. 15:24–32. 2006. View Article : Google Scholar : PubMed/NCBI


Zoch ML, Clemens TL and Riddle RC: New insights into the biology of osteocalcin. Bone. 82:42–49. 2016. View Article : Google Scholar


Cagman Z, Bingol Ozakpinar O, Cirakli Z, Gedikbasi A, Ay P, Colantonio D, Uras AR, Adeli K and Uras F: Reference intervals for growth arrest-specific 6 protein in adults. Scand J Clin Lab Invest. 77:109–114. 2017. View Article : Google Scholar : PubMed/NCBI


Varnum BC, Young C, Elliott G, Garcia A, Bartley TD, Fridell YW, Hunt RW, Trail G, Clogston C, Toso RJ, et al: Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature. 373:623–626. 1995. View Article : Google Scholar : PubMed/NCBI


Li M, Ye J, Zhao G, Hong G, Hu X, Cao K, Wu Y and Lu Z: Gas6 attenuates lipopolysaccharide-induced TNF-α expression and apoptosis in H9C2 cells through NF-κB and MAPK inhibition via the Axl/PI3K/Akt pathway. Int J Mol Med. 44:982–994. 2019.PubMed/NCBI


Tanabe K, Nagata K, Ohashi K, Nakano T, Arita H and Mizuno K: Roles of gamma-carboxylation and a sex hormone-binding globulin-like domain in receptor-binding and in biological activities of Gas6. FEBS Lett. 408:306–310. 1997. View Article : Google Scholar : PubMed/NCBI


Bellido-Martín L and de Frutos PG: Vitamin K-dependent actions of Gas6. Vitam Horm. 78:185–209. 2008. View Article : Google Scholar : PubMed/NCBI


Wu G, Ma Z, Cheng Y, Hu W, Deng C, Jiang S, Li T, Chen F and Yang Y: Targeting Gas6/TAM in cancer cells and tumor microenvironment. Mol Cancer. 17:202018. View Article : Google Scholar : PubMed/NCBI


Melaragno MG, Cavet ME, Yan C, Tai LK, Jin ZG, Haendeler J and Berk BC: Gas6 inhibits apoptosis in vascular smooth muscle: Role of Axl kinase and Akt. J Mol Cell Cardiol. 37:881–887. 2004. View Article : Google Scholar : PubMed/NCBI


McCloskey P, Fridell YW, Attar E, Villa J, Jin Y, Varnum B and Liu ET: GAS6 mediates adhesion of cells expressing the receptor tyrosine kinase Axl. J Biol Chem. 272:23285–23291. 1997. View Article : Google Scholar : PubMed/NCBI


Stenhoff J, Dahlbäck B and Hafizi S: Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochem Biophys Res Commun. 319:871–878. 2004. View Article : Google Scholar : PubMed/NCBI


Rizzoni D, Rizzoni M, Nardin M, Chiarini G, Agabiti-Rosei C, Aggiusti C, Paini A, Salvetti M and Muiesan ML: Vascular aging and disease of the small vessels. High Blood Press Cardiovasc Prev. 26:183–189. 2019. View Article : Google Scholar : PubMed/NCBI


Jin CW, Wang H, Chen YQ, Tang MX, Fan GQ, Wang ZH, Li L, Zhang Y, Zhang W and Zhong M: Gas6 delays senescence in vascular smooth muscle cells through the PI3K/Akt/FoxO signaling pathway. Cell Physiol Biochem. 35:1151–1166. 2015. View Article : Google Scholar


Clauser S, Meilhac O, Bièche I, Raynal P, Bruneval P, Michel JB and Borgel D: Increased secretion of Gas6 by smooth muscle cells in human atherosclerotic carotid plaques. Thromb Haemost. 107:140–149. 2012. View Article : Google Scholar


Holden RM, Hétu MF, Li TY, Ward EC, Couture LE, Herr JE, Christilaw E, Adams MA and Johri AM: Circulating Gas6 is associated with reduced human carotid atherosclerotic plaque burden in high risk cardiac patients. Clin Biochem. 64:6–11. 2019. View Article : Google Scholar


Tjwa M, Moons L and Lutgens E: Pleiotropic role of growth arrest-specific gene 6 in atherosclerosis. Curr Opin Lipidol. 20:386–392. 2009. View Article : Google Scholar : PubMed/NCBI


Meir KS and Leitersdorf E: Atherosclerosis in the apolipoprotein-E-deficient mouse: A decade of progress. Arterioscler Thromb Vasc Biol. 24:1006–1014. 2004. View Article : Google Scholar : PubMed/NCBI


Park JK, Theuer S, Kirsch T, Lindschau C, Klinge U, Heuser A, Plehm R, Todiras M, Carmeliet P, Haller H, et al: Growth arrest specific protein 6 participates in DOCA-induced target-organ damage. Hypertension. 54:359–364. 2009. View Article : Google Scholar : PubMed/NCBI


Zhao YF, Xu DC, Zhu GF, Zhu M, Tang K, Li WM and Xu YW: Growth arrest-specific 6 exacerbates pressure overload-induced cardiac hypertrophy. Hypertension. 67:118–129. 2016. View Article : Google Scholar


van der Meer JH, van der Poll T and van 't Veer C: TAM receptors, Gas6, and protein S: Roles in inflammation and hemostasis. Blood. 123:2460–2469. 2014. View Article : Google Scholar : PubMed/NCBI


Zhao GJ, Zheng JY, Bian JL, Chen LW, Dong N, Yu Y, Hong GL, Chandoo A, Yao YM and Lu ZQ: Growth arrest-specific 6 enhances the suppressive function of CD4+CD25+ regulatory T cells mainly through axl receptor. Mediators Inflamm. 2017:68484302017.


Haase VH: Mechanisms of hypoxia responses in renal tissue. J Am Soc Nephrol. 24:537–541. 2013. View Article : Google Scholar : PubMed/NCBI


Giangola MD, Yang WL, Rajayer SR, Kuncewitch M, Molmenti E, Nicastro J, Coppa GF and Wang P: Growth arrest-specific protein 6 protects against renal ischemia-reperfusion injury. J Surg Res. 199:572–579. 2015. View Article : Google Scholar : PubMed/NCBI


Ishimoto Y, Ohashi K, Mizuno K and Nakano T: Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. J Biochem. 127:411–417. 2000. View Article : Google Scholar : PubMed/NCBI


Lee IJ, Hilliard B, Swami A, Madara JC, Rao S, Patel T, Gaughan JP, Lee J, Gadegbeku CA, Choi ET and Cohen PL: Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure. Nephrol Dial Transplant. 27:4166–4172. 2012. View Article : Google Scholar : PubMed/NCBI


Hallajzadeh J, Ghorbanihaghjo A, Argani H, Dastmalchi S and Rashtchizadeh N: Growth arrest-specific 6 protein and matrix Gla protein in hemodialysis patients. Iran J Kidney Dis. 9:249–255. 2015.PubMed/NCBI


Panichi V, Migliori M, De Pietro S, Taccola D, Bianchi AM, Giovannini L, Norpoth M, Metelli MR, Cristofani R, Bertelli AAE, et al: C-reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure. Nephron. 91:594–600. 2002. View Article : Google Scholar : PubMed/NCBI


Weiner DE, Tabatabai S, Tighiouart H, Elsayed E, Bansal N, Griffith J, Salem DN, Levey AS and Sarnak MJ: Cardiovascular outcomes and all-cause mortality: Exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis. 48:392–401. 2006. View Article : Google Scholar : PubMed/NCBI


Silaghi CN, Ilyés T, Filip VP, Farca M, van Ballegooijen AJ and Crăciun AM: Vitamin K dependent proteins in kidney disease. Int J Mol Sci. 20:15712019. View Article : Google Scholar :


Wu CS, Hu CY, Tsai HF, Chyuan IT, Chan CJ, Chang SK and Hsu PN: Elevated serum level of growth arrest-specific protein 6 (Gas6) in systemic lupus erythematosus patients is associated with nephritis and cutaneous vasculitis. Rheumatol Int. 34:625–629. 2014. View Article : Google Scholar


Nagai K, Miyoshi M, Kake T, Fukushima N, Matsuura M, Shibata E, Yamada S, Yoshikawa K, Kanayama HO, Fukawa T, et al: Dual involvement of growth arrest-specific gene 6 in the early phase of human IgA nephropathy. PLoS One. 8:e667592013. View Article : Google Scholar : PubMed/NCBI


Nagai K, Arai H, Yanagita M, Matsubara T, Kanamori H, Nakano T, Iehara N, Fukatsu A, Kita T and Doi T: Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy. J Biol Chem. 278:18229–18234. 2003. View Article : Google Scholar : PubMed/NCBI


Nagai K, Matsubara T, Mima A, Sumi E, Kanamori H, Iehara N, Fukatsu A, Yanagita M, Nakano T, Ishimoto Y, et al: Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int. 68:552–561. 2005. View Article : Google Scholar : PubMed/NCBI


Hung YJ, Lee CH, Chu NF and Shieh YS: Plasma protein growth arrest-specific 6 levels are associated with altered glucose tolerance, inflammation, and endothelial dysfunction. Diabetes Care. 33:1840–1844. 2010. View Article : Google Scholar : PubMed/NCBI


Li W, Wang J, Ge L, Shan J, Zhang C and Liu J: Growth arrest-specific protein 6 (Gas6) as a noninvasive biomarker for early detection of diabetic nephropathy. Clin Exp Hypertens. 39:382–387. 2017. View Article : Google Scholar : PubMed/NCBI


Tian W, Wang L, Yuan L, Duan W, Zhao W, Wang S and Zhang Q: A prognostic risk model for patients with triple negative breast cancer based on stromal natural killer cells, tumor-associated macrophages and growth-arrest specific protein 6. Cancer Sci. 107:882–889. 2016. View Article : Google Scholar : PubMed/NCBI


Ammoun S, Provenzano L, Zhou L, Barczyk M, Evans K, Hilton DA, Hafizi S and Hanemann CO: Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival. Oncogene. 33:336–346. 2014. View Article : Google Scholar


Buehler M, Tse B, Leboucq A, Jacob F, Caduff R, Fink D, Goldstein DR and Heinzelmann-Schwarz V: Meta-analysis of microarray data identifies GAS6 expression as an independent predictor of poor survival in ovarian cancer. Biomed Res Int. 2013:2382842013. View Article : Google Scholar : PubMed/NCBI


Loges S, Schmidt T, Tjwa M, van Geyte K, Lievens D, Lutgens E, Vanhoutte D, Borgel D, Plaisance S, Hoylaerts M, et al: Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood. 115:2264–2273. 2010. View Article : Google Scholar


Waizenegger JS, Ben-Batalla I, Weinhold N, Meissner T, Wroblewski M, Janning M, Riecken K, Binder M, Atanackovic D, Taipaleenmaeki H, et al: Role of growth arrest-specific gene 6-Mer axis in multiple myeloma. Leukemia. 29:696–704. 2015. View Article : Google Scholar


Husain H, Scur M, Murtuza A, Bui N, Woodward B and Kurzrock R: Strategies to overcome bypass mechanisms mediating clinical resistance to EGFR tyrosine kinase inhibition in lung cancer. Mol Cancer Ther. 16:265–272. 2017. View Article : Google Scholar : PubMed/NCBI


Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, et al: The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 507:508–512. 2014. View Article : Google Scholar : PubMed/NCBI


Viegas CS, Simes DC, Laizé V, Williamson MK, Price PA and Cancela ML: Gla-rich protein (GRP), a new vitamin K-dependent protein identified from sturgeon cartilage and highly conserved in vertebrates. J Biol Chem. 283:36655–36664. 2008. View Article : Google Scholar : PubMed/NCBI


Viegas CS, Rafael MS, Enriquez JL, Teixeira A, Vitorino R, Luís IM, Costa RM, Santos S, Cavaco S, Neves J, et al: Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arterioscler Thromb Vasc Biol. 35:399–408. 2015. View Article : Google Scholar


Surmann-Schmitt C, Dietz U, Kireva T, Adam N, Park J, Tagariello A, Onnerfjord P, Heinegård D, Schlötzer-Schrehardt U, Deutzmann R, et al: Ucma, a novel secreted cartilage-specific protein with implications in osteogenesis. J Biol Chem. 283:7082–7093. 2008. View Article : Google Scholar


Neacsu CD, Grosch M, Tejada M, Winterpacht A, Paulsson M, Wagener R and Tagariello A: Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate γ-carboxylation. Matrix Biol. 30:369–378. 2011. View Article : Google Scholar : PubMed/NCBI


Cancela ML, Conceição N and Laizé V: Gla-rich protein, a new player in tissue calcification? Adv Nutr. 3:174–181. 2012. View Article : Google Scholar : PubMed/NCBI


Mackie EJ, Tatarczuch L and Mirams M: The skeleton: A multi-functional complex organ: The growth plate chondrocyte and endochondral ossification. J Endocrinol. 211:109–121. 2011. View Article : Google Scholar : PubMed/NCBI


Granadeiro L, Dirks RP, Ortiz-Delgado JB, Gavaia PJ, Sarasquete C, Laizé V, Cancela ML and Fernández I: Warfarin-exposed zebrafish embryos resembles human warfarin embryopathy in a dose and developmental-time dependent manner-from molecular mechanisms to environmental concerns. Ecotoxicol Environ Saf. 181:559–571. 2019. View Article : Google Scholar : PubMed/NCBI


R Sousa A, Barreira R and Santos E: Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome. BMJ Case Rep. 2018:bcr20172231592018. View Article : Google Scholar


Maruotti N, Corrado A and Cantatore FP: Osteoblast role in osteoarthritis pathogenesis. J Cell Physiol. 232:2957–2963. 2017. View Article : Google Scholar : PubMed/NCBI


Sanchez C, Deberg MA, Piccardi N, Msika P, Reginster JYL and Henrotin YE: Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 13:988–997. 2005. View Article : Google Scholar : PubMed/NCBI


Sokolove J and Lepus CM: Role of inflammation in the pathogenesis of osteoarthritis: Latest findings and interpretations. Ther Adv Musculoskelet Dis. 5:77–94. 2013. View Article : Google Scholar : PubMed/NCBI


Okuyan HM, Terzi MY, Ozcan O and Kalaci A: Association of UCMA levels in serum and synovial fluid with severity of knee osteoarthritis. Int J Rheum Dis. 22:1884–1890. 2019. View Article : Google Scholar : PubMed/NCBI


Misra D, Booth SL, Tolstykh I, Felson DT, Nevitt MC, Lewis CE, Torner J and Neogi T: Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med. 126:243–248. 2013. View Article : Google Scholar : PubMed/NCBI


Hunt JL, Fairman R, Mitchell ME, Carpenter JP, Golden M, Khalapyan T, Wolfe M, Neschis D, Milner R, Scoll B, et al: Bone formation in carotid plaques: A clinicopathological study. Stroke. 33:1214–1219. 2002. View Article : Google Scholar : PubMed/NCBI


Cozzolino M, Fusaro M, Ciceri P, Gasperoni L and Cianciolo G: The role of vitamin K in vascular calcification. Adv Chronic Kidney Dis. 26:437–444. 2019. View Article : Google Scholar : PubMed/NCBI


Hruska KA: Vascular smooth muscle cells in the pathogenesis of vascular calcification. Circ Res. 104:710–711. 2009. View Article : Google Scholar : PubMed/NCBI


Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, Tordoir JH, Spronk HM, Vermeer C and Daemen MJ: Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 21:1998–2003. 2001. View Article : Google Scholar : PubMed/NCBI


Kapustin AN and Shanahan CM: Calcium regulation of vascular smooth muscle cell-derived matrix vesicles. Trends Cardiovasc Med. 22:133–137. 2012. View Article : Google Scholar : PubMed/NCBI


Kapustin AN, Davies JD, Reynolds JL, McNair R, Jones GT, Sidibe A, Schurgers LJ, Skepper JN, Proudfoot D, Mayr M and Shanahan CM: Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res. 109:e1–e12. 2011. View Article : Google Scholar : PubMed/NCBI


Toroian D, Lim JE and Price PA: The size exclusion characteristics of type I collagen: Implications for the role of noncollagenous bone constituents in mineralization. J Biol Chem. 282:22437–22447. 2007. View Article : Google Scholar : PubMed/NCBI


Price PA, Toroian D and Lim JE: Mineralization by inhibitor exclusion: The calcification of collagen with fetuin. J Biol Chem. 284:17092–17101. 2009. View Article : Google Scholar : PubMed/NCBI


New SEP and Aikawa E: Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res. 108:1381–1391. 2011. View Article : Google Scholar : PubMed/NCBI


Ikeda K, Souma Y, Akakabe Y, Kitamura Y, Matsuo K, Shimoda Y, Ueyama T, Matoba S, Yamada H, Okigaki M and Matsubara H: Macrophages play a unique role in the plaque calcification by enhancing the osteogenic signals exerted by vascular smooth muscle cells. Biochem Biophys Res Commun. 425:39–44. 2012. View Article : Google Scholar : PubMed/NCBI


New SEP, Goettsch C, Aikawa M, Marchini JF, Shibasaki M, Yabusaki K, Libby P, Shanahan CM, Croce K and Aikawa E: Macrophage-derived matrix vesicles: An alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res. 113:72–77. 2013. View Article : Google Scholar : PubMed/NCBI


Evrard S, Delanaye P, Kamel S, Cristol JP and Cavalier E: SFBC/SN joined working group on vascular calcifications: Vascular calcification: From pathophysiology to biomarkers. Clin Chim Acta. 438:401–414. 2015. View Article : Google Scholar


Tesfamariam B: Involvement of vitamin K-dependent proteins in vascular calcification. J Cardiovasc Pharmacol Ther. 24:323–333. 2019. View Article : Google Scholar : PubMed/NCBI


Viegas CSB, Santos L, Macedo AL, Matos AA, Silva AP, Neves PL, Staes A, Gevaert K, Morais R, Vermeer C, et al: Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification: A role for GRP (Gla-Rich Protein). Arterioscler Thromb Vasc Biol. 38:575–587. 2018. View Article : Google Scholar : PubMed/NCBI


Pasch A, Farese S, Gräber S, Wald J, Richtering W, Floege J and Jahnen-Dechent W: Nanoparticle-based test measures overall propensity for calcification in serum. J Am Soc Nephrol. 23:1744–1752. 2012. View Article : Google Scholar : PubMed/NCBI


Viegas CSB, Costa RM, Santos L, Videira PA, Silva Z, Araújo N, Macedo AL, Matos AP, Vermeer C and Simes DC: Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases. PLoS One. 12:e01778292017. View Article : Google Scholar : PubMed/NCBI


Willems BA, Furmanik M, Caron MMJ, Chatrou MLL, Kusters DHM, Welting TJM, Stock M, Rafael MS, Viegas CSB, Simes DC, et al: Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling. Sci Rep. 8:49612018. View Article : Google Scholar : PubMed/NCBI


Karamouzis MV, Likaki-Karatza E, Ravazoula P, Badra FA, Koukouras D, Tzorakoleftherakis E, Papavassiliou AG and Kalofonos HP: Non-palpable breast carcinomas: Correlation of mammographically detected malignant-appearing microcalcifications and molecular prognostic factors. Int J Cancer. 102:86–90. 2002. View Article : Google Scholar : PubMed/NCBI


Kim JH, Ko ES, Kim DY, Han H, Sohn JH and Choe DH: Noncalcified ductal carcinoma in situ: Imaging and histologic findings in 36 tumors. J Ultrasound Med. 28:903–910. 2009. View Article : Google Scholar : PubMed/NCBI


Avdan Aslan A, Gültekin S, Esendağli Yilmaz G and Kurukahvecioğlu O: Is there any association between mammographic features of microcalcifications and breast cancer subtypes in ductal carcinoma in situ? Acad Radiol. Jun 30–2020.Online ahead of print. View Article : Google Scholar : PubMed/NCBI


Viegas CS, Herfs M, Rafael MS, Enriquez JL, Teixeira A, Luís IM, van 't Hoofd CM, João A, Maria VL, Cavaco S, et al: Gla-rich protein is a potential new vitamin K target in cancer: Evidences for a direct GRP-mineral interaction. Biomed Res Int. 2014:3402162014. View Article : Google Scholar : PubMed/NCBI


Huisse MG, Leclercq M, Belghiti J, Flejou JF, Suttie JW, Bezeaud A, Stafford DW and Guillin MC: Mechanism of the abnormal vitamin K-dependent gamma-carboxylation process in human hepatocellular carcinomas. Cancer. 74:1533–1541. 1994. View Article : Google Scholar : PubMed/NCBI


Pasierski T: Vitamin K antagonists in anticoagulant therapy of patients with cancer. Pol Arch Med Wewn. 122:60–64. 2012.PubMed/NCBI


Vermeer C: Vitamin K: The effect on health beyond coagulation-an overview. Food Nutr Res. 56:2012. View Article : Google Scholar


Cox RF, Hernandez-Santana A, Ramdass S, McMahon G, Harmey JH and Morgan MP: Microcalcifications in breast cancer: Novel insights into the molecular mechanism and functional consequence of mammary mineralisation. Br J Cancer. 106:525–537. 2012. View Article : Google Scholar : PubMed/NCBI


Takeshita S, Kikuno R, Tezuka K and Amann E: Osteoblast-specific factor 2: Cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Biochem J. 294:271–278. 1993. View Article : Google Scholar : PubMed/NCBI


Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD and Galipeau J: Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells. J Biol Chem. 283:17991–8001. 2008. View Article : Google Scholar : PubMed/NCBI


Zhong H, Li X, Zhang J and Wu X: Overexpression of periostin is positively associated with gastric cancer metastasis through promoting tumor metastasis and invasion. J Cell Biochem. 120:9927–9935. 2019. View Article : Google Scholar : PubMed/NCBI


Nakazawa T, Nakajima A, Seki N, Okawa A, Kato M, Moriya H, Amizuka N, Einhorn TA and Yamazaki M: Gene expression of periostin in the early stage of fracture healing detected by cDNA microarray analysis. J Orthop Res. 22:520–525. 2004. View Article : Google Scholar : PubMed/NCBI


Li W, Gao P, Zhi Y, Xu W, Wu Y, Yin J and Zhang J: Periostin: Its role in asthma and its potential as a diagnostic or therapeutic target. Respir Res. 16:572015. View Article : Google Scholar : PubMed/NCBI


Duchamp de Lageneste O and Colnot C: Periostin in bone regeneration. Adv Exp Med Biol. 1132:49–61. 2019. View Article : Google Scholar : PubMed/NCBI


Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC and Einhorn TA: Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res. 87:107–118. 2008. View Article : Google Scholar : PubMed/NCBI


Einhorn TA and Gerstenfeld LC: Fracture healing: Mechanisms and interventions. Nat Rev Rheumatol. 11:45–54. 2015. View Article : Google Scholar :


Zhang X, Xie C, Lin AS, Ito H, Awad H, Lieberman JR, Rubery PT, Schwarz EM, O'Keefe RJ and Guldberg RE: Periosteal progenitor cell fate in segmental cortical bone graft transplantations: Implications for functional tissue engineering. J Bone Miner Res. 20:2124–2137. 2005. View Article : Google Scholar : PubMed/NCBI


Neagu TP, Ţigliş M, Cocoloş I and Jecan CR: The relationship between periosteum and fracture healing. Rom J Morphol Embryol. 57:1215–1220. 2016.


Kudo A: Periostin in bone biology. Adv Exp Med Biol. 1132:43–47. 2019. View Article : Google Scholar : PubMed/NCBI


Allen MR, Hock JM and Burr DB: Periosteum: Biology, regulation, and response to osteoporosis therapies. Bone. 35:1003–1012. 2004. View Article : Google Scholar : PubMed/NCBI


Kashima TG, Nishiyama T, Shimazu K, Shimazaki M, Kii I, Grigoriadis AE, Fukayama M and Kudo A: Periostin, a novel marker of intramembranous ossification, is expressed in fibrous dysplasia and in c-Fos-overexpressing bone lesions. Hum Pathol. 40:226–237. 2009. View Article : Google Scholar


Varughese R, Semprini R, Munro C, Fingleton J, Holweg C, Weatherall M, Beasley R and Braithwaite I: Serum periostin levels following small bone fractures, long bone fractures and joint replacements: An observational study. Allergy Asthma Clin Immunol. 14:302018. View Article : Google Scholar : PubMed/NCBI


Roberts SJ, van Gastel N, Carmeliet G, Carmeliet G and Luyten FP: Uncovering the periosteum for skeletal regeneration: The stem cell that lies beneath. Bone. 70:10–18. 2015. View Article : Google Scholar


Matsuzawa M, Arai C, Nomura Y, Murata T, Yamakoshi Y, Oida S, Hanada N and Nakamura Y: Periostin of human periodontal ligament fibroblasts promotes migration of human mesenchymal stem cell through the αvβ3 integrin/FAK/PI3K/Akt pathway. J Periodont Res. 50:855–863. 2015. View Article : Google Scholar


Hwang EY, Jeong MS, Park EK, Kim JH and Jang SB: Structural characterization and interaction of periostin and bone morphogenetic protein for regulation of collagen cross-linking. Biochem Biophys Res Commun. 449:425–431. 2014. View Article : Google Scholar : PubMed/NCBI


Rezaieyazdi Z, Falsoleiman H, Khajehdaluee M, Saghafi M and Mokhtari-Amirmajdi E: Reduced bone density in patients on long-term warfarin. Int J Rheum Dis. 12:130–135. 2009. View Article : Google Scholar


Tufano A, Coppola A, Contaldi P, Franchini M and Minno GD: Oral anticoagulant drugs and the risk of osteoporosis: New anticoagulants better than old? Semin Thromb Hemost. 41:382–388. 2015. View Article : Google Scholar : PubMed/NCBI


Jeong HM, Cho DH, Jin YH, Chung JO, Chung MY, Chung DJ and Lee KY: Inhibition of osteoblastic differentiation by warfarin and 18-α-glycyrrhetinic acid. Arch Pharm Res. 34:1381–1387. 2011. View Article : Google Scholar : PubMed/NCBI


Verma D, Kumar R, Pereira RS, Karantanou C, Zanetti C, Minciacchi VR, Fulzele K, Kunz K, Hoelper S, Zia-Chahabi S, et al: Vitamin K antagonism impairs the bone marrow microenvironment and hematopoiesis. Blood. 134:227–238. 2019. View Article : Google Scholar : PubMed/NCBI


Sugimoto I, Hirakawa K, Ishino T, Takeno S and Yajin K: Vitamin D3, vitamin K2, and warfarin regulate bone metabolism in human paranasal sinus bones. Rhinology. 45:208–213. 2007.PubMed/NCBI


Rousseau JC, Sornay-Rendu E, Bertholon C, Chapurlat R and Garnero P: Serum periostin is associated with fracture risk in postmenopausal women: A 7-year prospective analysis of the OFELY study. J Clin Endocrinol Metab. 99:2533–2539. 2014. View Article : Google Scholar : PubMed/NCBI


Kim BJ, Rhee Y, Kim CH, Baek KH, Min YK, Kim DY, Ahn SH, Kim H, Lee SH, Lee SY, et al: Plasma periostin associates significantly with non-vertebral but not vertebral fractures in post-menopausal women: Clinical evidence for the different effects of periostin depending on the skeletal site. Bone. 81:435–441. 2015. View Article : Google Scholar : PubMed/NCBI


Rousseau JC, Sornay-Rendu E, Bertholon C, Garnero P and Chapurlat R: Serum periostin is associated with prevalent knee osteoarthritis and disease incidence/progression in women: The OFELY study. Osteoarthr Cartil. 23:1736–1742. 2015. View Article : Google Scholar


Snider P, Hinton RB, Moreno-Rodriguez RA, Wang J, Rogers R, Lindsley A, Li F, Ingram DA, Menick D, Field L, et al: Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ Res. 102:752–760. 2008. View Article : Google Scholar : PubMed/NCBI


Nagaraju CK, Robinson EL, Abdesselem M, Trenson S, Dries E, Gilbert G, Janssens S, Van Cleemput J, Rega F, Meyns B, et al: Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J Am Coll Cardiol. 73:2267–2282. 2019. View Article : Google Scholar : PubMed/NCBI


Zheng X, Wang S, Zou X, Jing Y, Yang R, Li S and Wang F: Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp Anim. 66:217–228. 2017. View Article : Google Scholar : PubMed/NCBI


Chen Z, Xie J, Hao H, Lin H, Wang L, Zhang Y, Chen L, Cao S, Huang X, Liao W, et al: Ablation of periostin inhibits post-infarction myocardial regeneration in neonatal mice mediated by the phosphatidylinositol 3 kinase/glycogen synthase kinase 3β/cyclin D1 signalling pathway. Cardiovasc Res. 113:620–632. 2017. View Article : Google Scholar : PubMed/NCBI


Hixson JE, Shimmin LC, Montasser ME, Kim DK, Zhong Y, Ibarguen H, Follis J, Malcom G, Strong J, Howard T, et al: Common variants in the periostin gene influence development of atherosclerosis in young persons. Arterioscler Thromb Vasc Biol. 31:1661–1667. 2011. View Article : Google Scholar : PubMed/NCBI


Hakuno D, Kimura N, Yoshioka M, Mukai M, Kimura T, Okada Y, Yozu R, Shukunami C, Hiraki Y, Kudo A, et al: Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents. J Clin Invest. 120:2292–2306. 2010. View Article : Google Scholar : PubMed/NCBI


Lindner V, Wang Q, Conley BA, Friesel RE and Vary CP: Vascular injury induces expression of periostin: Implications for vascular cell differentiation and migration. Arterioscler Thromb Vasc Biol. 25:77–83. 2005. View Article : Google Scholar


Schwanekamp JA, Lorts A, Vagnozzi RJ, Vanhoutte D and Molkentin JD: Deletion of periostin protects against atherosclerosis in mice by altering inflammation and extracellular matrix remodeling. Arterioscler Thromb Vasc Biol. 36:60–68. 2016. View Article : Google Scholar


Ahlfeld SK, Gao Y, Wang J, Horgusluoglu E, Bolanis E, Clapp DW and Conway SJ: Periostin downregulation is an early marker of inhibited neonatal murine lung alveolar septation. Birth Defects Res A Clin Mol Teratol. 97:373–385. 2013. View Article : Google Scholar : PubMed/NCBI


Bozyk PD, Bentley JK, Popova AP, Anyanwu AC, Linn MD, Goldsmith AM, Pryhuber GS, Moore BB and Hershenson MB: Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication. PLoS One. 7:e313362012. View Article : Google Scholar : PubMed/NCBI


Naik PK, Bozyk PD, Bentley JK, Popova AP, Birch CM, Wilke CA, Fry CD, White ES, Sisson TH, Tayob N, et al: Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 303:L1046–L1056. 2012. View Article : Google Scholar : PubMed/NCBI


Kanemitsu Y, Suzuki M, Fukumitsu K, Asano T, Takeda N, Nakamura Y, Ozawa Y, Masaki A, Ono J, Kurokawa R, et al: A novel pathophysiologic link between upper and lower airways in patients with chronic rhinosinusitis: Association of sputum periostin levels with upper airway inflammation and olfactory function. World Allergy Organ J. 13:1000942020. View Article : Google Scholar : PubMed/NCBI


Katoh S, Matsumoto N, Tanaka H, Yasokawa N, Kittaka M, Kurose K, Abe M, Yoshioka D, Shirai R, Nakazato M and Kobashi Y: Elevated levels of periostin and TGF-β1 in the bronchoalveolar lavage fluid of patients with idiopathic eosinophilic pneumonia. Asian Pac J Allergy Immunol. 38:208–213. 2020.


Tanaka J, Hebisawa A, Oguma T, Tomomatsu K, Suzuki J, Shimizu H, Kawabata Y, Ishiguro T, Takayanagi N, Ueda S, et al: Evaluating serum periostin levels in allergic bronchopulmonary aspergillosis. Allergy. 75:974–977. 2020. View Article : Google Scholar


Wilson MS and Wynn TA: Pulmonary fibrosis: Pathogenesis, etiology and regulation. Mucosal Immunol. 2:103–121. 2009. View Article : Google Scholar : PubMed/NCBI


Behr J, Kreuter M, Hoeper MM, Wirtz H, Klotsche J, Koschel D, Andreas S, Claussen M, Grohé C, Wilkens H, et al: Management of patients with idiopathic pulmonary fibrosis in clinical practice: The INSIGHTS-IPF registry. Eur Respir J. 46:186–196. 2015. View Article : Google Scholar : PubMed/NCBI


Okamoto M, Hoshino T, Kitasato Y, Sakazaki Y, Kawayama T, Fujimoto K, Ohshima K, Shiraishi H, Uchida M, Ono J, et al: Periostin, a matrix protein, is a novel biomarker for idiopathic interstitial pneumonias. Eur Respir J. 37:1119–1127. 2011. View Article : Google Scholar


Nance T, Smith KS, Anaya V, Richardson R, Ho L, Pala M, Mostafavi S, Battle A, Feghali-Bostwick C, Rosen G and Montgomery SB: Transcriptome analysis reveals differential splicing events in IPF lung tissue. PLoS One. 9:e975502014. View Article : Google Scholar : PubMed/NCBI


Ashley SL, Wilke CA, Kim KK and Moore BB: Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis. Mucosal Immunol. 10:341–351. 2017. View Article : Google Scholar :


Yoshihara T, Nanri Y, Nunomura S, Yamaguchi Y, Feghali-Bostwick C, Ajito K, Murakami S, Mawatari M and Izuhara K: Periostin plays a critical role in the cell cycle in lung fibroblasts. Respir Res. 21:382020. View Article : Google Scholar : PubMed/NCBI


Nanri Y, Nunomura S, Terasaki Y, Yoshihara T, Hirano Y, Yokosaki Y, Yamaguchi Y, Feghali-Bostwick C, Ajito K, Murakami S, et al: Cross-talk between transforming growth factor-beta and periostin can be targeted for pulmonary fibrosis. Am J Respir Cell Mol Biol. 62:204–216. 2020. View Article : Google Scholar


De Brouwer B, Piscaer I, Von Der Thusen JH, Grutters JC, Schutgens RE, Wouters EF and Janssen R: Should vitamin K be supplemented instead of antagonised in patients with idiopathic pulmonary fibrosis? Expert Rev Respir Med. 12:169–175. 2018. View Article : Google Scholar : PubMed/NCBI


Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, et al: Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA. 104:15858–15863. 2007. View Article : Google Scholar : PubMed/NCBI


Izuhara K, Nunomura S, Nanri Y, Ogawa M, Ono J, Mitamura Y and Yoshihara T: Periostin in inflammation and allergy. Cell Mol Life Sci. 74:4293–4303. 2017. View Article : Google Scholar : PubMed/NCBI


Tartibi HM and Bahna SL: Clinical and biological markers of asthma control. Expert Rev Clin Immunol. 10:1453–1461. 2014. View Article : Google Scholar : PubMed/NCBI


Johansson MW, Annis DS and Mosher DF: α(M)β(2) integrin-mediated adhesion and motility of IL-5-stimulated eosinophils on periostin. Am J Respir Cell Mol Biol. 48:503–510. 2013. View Article : Google Scholar : PubMed/NCBI


Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, Muller SJ and Fahy JV: Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci USA. 107:14170–14175. 2010. View Article : Google Scholar : PubMed/NCBI


Kimur I, Tanizaki Y, Sato S, Saito K and Takahashi K: Menaquinone (vitamin K2) therapy for bronchial asthma. II. Clinical effect of menaquinone on bronchial asthma. Acta medica Okayama. 29:127–135. 1975.PubMed/NCBI


Litonjua AA: Fat-soluble vitamins and atopic disease: What is the evidence? Proc Nutr Soc. 71:67–74. 2012. View Article : Google Scholar :


El Basha NR, Osman HM, Abdelaal AA, Saed SM and Shaaban HH: Increased expression of serum periostin and YKL40 in children with severe asthma and asthma exacerbation. J Investig Med. 66:1102–1108. 2018. View Article : Google Scholar : PubMed/NCBI


Matsusaka M, Kabata H, Fukunaga K, Suzuki Y, Masaki K, Mochimaru T, Sakamaki F, Oyamada Y, Inoue T, Oguma T, et al: Phenotype of asthma related with high serum periostin levels. Allergol Int. 64:175–180. 2015. View Article : Google Scholar : PubMed/NCBI


Kim MA, Izuhara K, Ohta S, Ono J, Yoon MK, Ban GY, Yoo HS, Shin YS, Ye YM, Nahm DH and Park HS: Association of serum periostin with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 113:314–320. 2014. View Article : Google Scholar : PubMed/NCBI


Asano T, Kanemitsu Y, Takemura M, Yokota M, Fukumitsu K, Takeda N, Ichikawa H, Uemura T, Takakuwa O, Ohkubo H, et al: Serum periostin as a biomarker for comorbid chronic rhinosinusitis in patients with asthma. Ann Am Thorac Soc. 14:667–675. 2017. View Article : Google Scholar : PubMed/NCBI


Cianchetti S, Cardini C, Puxeddu I, Latorre M, Bartoli ML, Bradicich M, Dente F, Bacci E, Celi A and Paggiaro P: Distinct profile of inflammatory and remodelling biomarkers in sputum of severe asthmatic patients with or without persistent airway obstruction. World Allergy Organ J. 12:1000782019. View Article : Google Scholar : PubMed/NCBI


Li Y, Chen JP, Duan L and Li S: Effect of vitamin K2 on type 2 diabetes mellitus: A review. Diabetes Res Clin Pract. 136:39–51. 2018. View Article : Google Scholar


Mukai K, Morimoto H, Kikuchi S and Nagaoka S: Kinetic study of free-radical-scavenging action of biological hydroquinones (reduced forms of ubiquinone, vitamin K and tocopherol quinone) in solution. Biochim Biophys Acta. 1157:313–317. 1993. View Article : Google Scholar : PubMed/NCBI


Westhofen P, Watzka M, Marinova M, Hass M, Kirfel G, Müller J, Bevans CG, Müller CR and Oldenburg J: Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular anti-oxidant function. J Biol Chem. 286:15085–15094. 2011. View Article : Google Scholar : PubMed/NCBI


Vos M, Esposito G, Edirisinghe JN, Vilain S, Haddad DM, Slabbaert JR, Van Meensel S, Schaap O, De Strooper B, Meganathan R, et al: Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science. 336:1306–1310. 2012. View Article : Google Scholar : PubMed/NCBI


Fujii S, Shimizu A, Takeda N, Oguchi K, Katsurai T, Shirakawa H, Komai M and Kagechika H: Systematic synthesis and anti-inflammatory activity of ω-carboxylated menaquinone derivatives-investigations on identified and putative vitamin K2 metabolites. Bioorg Med Chem. 23:2344–2352. 2015. View Article : Google Scholar : PubMed/NCBI


Myneni VD and Mezey E: Immunomodulatory effect of vitamin K2: Implications for bone health. Oral Dis. 24:67–71. 2018. View Article : Google Scholar : PubMed/NCBI


Ishizuka M, Kubota K, Shimoda M, Kita J, Kato M, Park KH and Shiraki T: Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: A prospective randomized controlled trial. Anticancer Res. 32:5415–5420. 2012.PubMed/NCBI


Zhong JH, Mo XS, Xiang BD, Yuan WP, Jiang JF, Xie GS and Li LQ: Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS One. 8:e580822013. View Article : Google Scholar : PubMed/NCBI


Enomoto M, Tsuchida A, Miyazawa K, Yokoyama T, Kawakita H, Tokita H, Naito M, Itoh M, Ohyashiki K and Aoki T: Vitamin K2-induced cell growth inhibition via autophagy formation in cholangiocellular carcinoma cell lines. Int J Mol Med. 20:801–808. 2007.PubMed/NCBI


Sibayama-Imazu T, Fujisawa Y, Masuda Y, Aiuchi T, Nakajo S, Itabe H and Nakaya K: Induction of apoptosis in PA-1 ovarian cancer cells by vitamin K2 is associated with an increase in the level of TR3/Nur77 and its accumulation in mitochondria and nuclei. J Cancer Res Clin Oncol. 134:803–812. 2008. View Article : Google Scholar : PubMed/NCBI


Showalter SL, Wang Z, Costantino CL, Witkiewicz AK, Yeo CJ, Brody JR and Carr BI: Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway. J Gastroenterol Hepatol. 25:738–744. 2010. View Article : Google Scholar


Xv F, Chen J, Duan L and Li S: Research progress on the anticancer effects of vitamin K2. Oncol Lett. 15:8926–8934. 2018.PubMed/NCBI

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Xiao H, Chen J, Duan L and Li S: Role of emerging vitamin K‑dependent proteins: Growth arrest‑specific protein 6, Gla‑rich protein and periostin (Review). Int J Mol Med 47: 2, 2021
Xiao, H., Chen, J., Duan, L., & Li, S. (2021). Role of emerging vitamin K‑dependent proteins: Growth arrest‑specific protein 6, Gla‑rich protein and periostin (Review). International Journal of Molecular Medicine, 47, 2.
Xiao, H., Chen, J., Duan, L., Li, S."Role of emerging vitamin K‑dependent proteins: Growth arrest‑specific protein 6, Gla‑rich protein and periostin (Review)". International Journal of Molecular Medicine 47.3 (2021): 2.
Xiao, H., Chen, J., Duan, L., Li, S."Role of emerging vitamin K‑dependent proteins: Growth arrest‑specific protein 6, Gla‑rich protein and periostin (Review)". International Journal of Molecular Medicine 47, no. 3 (2021): 2.