Osteoporosis is a systemic bone disease characterized by decreased bone mass and quality and bone micro-architecture degradation. Its primary cause is disorder of bone metabolism: Over-formation of osteoclasts, resulting in increased bone resorption and insufficient osteogenesis. Traditional herbal flavonoids can be used as alternative drugs to prevent and treat osteoporosis due to their wide range of sources, structural diversity and less adverse effects. The present paper reviewed six flavonoids, including quercetin, icariin, hesperitin, naringin, chrysin and pueraria, that promote bone formation and have been widely studied in the literature over the past five years, with the aim of providing novel ideas for the development of drugs for bone-associated disease.
flavonoidquercetinicariinhesperetinnaringinchrysinPuerarinKey Laboratory of Shanxi ProvinceKF2020-02The present study was supported by open project of Key Laboratory of Shanxi Province (grant no. KF2020-02).Introduction
Osteoporosis is a systemic bone disease characterised by low bone mass and degeneration of bone tissue micro-architecture, leading to increased bone fragility and susceptibility to fractures (1). Strategies to prevent and treat osteoporosis include preventive (such as increased vitamin D and protein intake, exercise, smoking cessation, avoidance of excessive alcohol intake and prevention of falls) and therapeutic measures (2). Clinically used drugs include bisphosphonates (such as alendronate, risedronate and ibandronate), antibodies against nuclear factor-κB ligand receptor activator (RANKL; for example, denosumab), selective oestrogen receptor modulators (SERMs; for example, raloxifene), parathyroid hormone (PTH), PTH-related peptides (such as teriparatide and abaloparatide) and calcitonin (such as salmon calcitonin). However, clinical use of most anti-bone resorption drugs is limited by side effects of long-term inhibition of bone resorption, such as upper gastrointestinal bleeding, acute-phase reaction, hypocalcaemia, secondary hyperparathyroidism and most drugs on the market are expensive (3,4). With the ageing world population, the incidence of osteoporosis is increasing annually, with an increase of 70.1% in 2019 compared with 1990, endangering quality of life of middle-aged and older adults and imposing a burden on society and families (5).
Flavonoids are compounds formed when two benzene rings (A and B rings) are joined by a pyran heterocyclic ring (C ring) consisting of a central three-carbon chain (6). The compounds are found in the roots, stems, leaves, fruit and seeds of plants such as strawberries, onions and cucumbers (7). Flavonoids are diverse in structure and most are similar to oestrogen and exert anti-inflammatory, antibacterial, anti-cancer, antioxidant, osteogenic, osteoclast-inhibitory and oestrogen-like effects (8).
Multiple studies have confirmed that flavonoids have a promoting effect on osteogenesis and the underlying mechanism has received attention and become a hotspot in developing novel osteoporosis drugs (9,10). The present review focused on the role of flavonoids in osteoporosis.
Definition of osteoporosis, diagnostic criteria and epidemiological investigation
According to the World Health Organization (WHO), osteoporosis is defined as a bone disease characterized by a decrease in bone strength that puts a person at increased risk of fracture. Bone strength primarily reflects a combination of bone density and bone mass. The majority of the patient population with this disease is postmenopausal women (11). Postmenopausal osteoporosis is defined as bone density that is ≤2.5 standard deviations the mean for women aged 25-50 years. (T-score ≤2.5) (12,13). Therefore, clinical diagnosis and assessment of osteoporosis are based on measuring bone mineral density (BMD) (14). The results of an epidemiological survey on osteoporosis conducted by the National Health Council of China in 2019 demonstrated that the prevalence of osteoporosis in China is 3.2 for those aged 40-49, 19.2 for those aged 50-64 years and 32.0% for those aged ≥65 years (15). In the United States, ~10 million people aged >50 years have osteoporosis (16). In the United Kingdom, 50% of women and 20% of men aged >50 years suffer from osteoporotic fractures (17,18). Fragility fractures caused by osteoporosis lead to increased morbidity and mortality, resulting in a social burden (19). Thus, research on the prevention and treatment of osteoporosis has become an urgent priority (20).
Pharmacological studies of flavonoids
Flavonoids are compounds that are widely found in nature, and so far, >9,000 flavonoids have been reported (21,22) Flavonoids comprise subclasses, including flavonoids (such as lignans, rutin, bryophyllin and baicalin), flavanones (such as naringenin and hesperidin), isoflavones (such as soy flavonoids and genistein), pro-anthocyanidins, flavanols (such as catechins and epicatechin) and flavonols (such as kaempferol, yohimbine and quercetin), which all have a basic flavan structure (2-phenylchroman) (23). The present review focuses on six well-studied flavonoids (Fig. 1).
Quercetin
Quercetin is derived from the genus Quercus and has been used as a dietary supplement since 1857 (24,25). It has been isolated from >20 plant materials in the United States, Europe, Asia and South Africa (26–28). Moreover, it is present in fruits and vegetables, such as onions, tomatoes, peppers, lettuce, radish leaves, papaya, grapes, oranges and strawberries, as well as many seeds, nuts (including almonds and pistachios), flowers, bark and leaves (26,29–37). Quercetin is a key flavonol, accounting for the highest percentage of total dietary flavonoid intake (38). Quercetin is 3,3,4,5,7-penthydroxy flavonoid and most other flavonoids exhibit this basic structure (39,40). Due to the presence of phenolic hydroxyl groups and double bonds, quercetin exhibits antioxidant activity (41). It exerts pharmacological activity, such as anti-cancer, anti-inflammatory and antimicrobial activity, as well as anti-ulcer, anti-allergy, antitumor, anti-viral, anti-diabetic, anti-hypertensive, anti-infective, stomach-protective and immunomodulatory effects and protects against bone loss (42,43).
Icariin (ICA)
With the development of modern separation techniques and ethnopharmacology, increasing evidence has shown that ICA is one of the primary biologically active monomers extracted from Epimedium (44,45). Epimedium, also known as Ninebark, was recorded 400 years ago in the traditional Chinese medical text Shennong Ben Cao Jing and is used in various herbal formulations (46). The herb is considered a complementary and alternative medicine and has been demonstrated to possess therapeutic effects in fractures, joint disease and gonadal dysfunction (36). There are >40 species of the genus worldwide, primarily found in southwest and central China, with a total of 27 species and four varieties, accounting for ~70% of the total global number (47). More than 260 components have been extracted from Epimedium, including 141 flavonoids and 31 lignans. Among them, flavonoid glycosides have been identified as key pharmacologically active ingredients (48,49). ICA is the primary active ingredient of Epimedium and was selected as a chemical marker for quality control of Epimedium in the Chinese Pharmacopoeia (44). It is a light-yellow powder with a molecular formula of C33H40O15 and a molecular weight of 676.67 g/mol. ICA has a variety of pharmacological activities, including anti-inflammatory, anti-oxidant, anti-cancer, anti-osteoporosis, anti-hepatotoxic, anti-depressant and neuroprotective effects and protects against cardiac ischaemia and atherosclerosis (50,51).
Hesperitin
Hesperitin (3′,5,-trihydroxy-4-methyl-7-xanthone) is a key component of citrus plants in the Rutaceae family. It has the molecular formula C16H14O6 and is a member of the flavonoid subclass flavones, primarily found in citrus fruits (52). Like most flavonoids, hesperetin naturally occurs in the form of glycosides, known as hesperidin, first isolated from citrus peel by the French chemist Le Breton (53). Citrus bioflavonoids (including hesperidin) appear safe and do not cause side effects even during pregnancy. Dietary hesperidin is deglycosylated to hesperetin by intestinal bacteria before absorption (54,55). Its structure consists of ketone carbonyl, ether, methoxy and phenolic hydroxyl groups, allowing for a wide range of pharmacological effects, such as antioxidant, anti-allergic, and anti-inflammatory effects (56–59).
Naringin
Naringin is a flavonoid and key secondary metabolite. Bioactive naringin compounds are found in plant-based foods, such as vegetables, fruit, tea and wine (60). Naringin-derived drugs are used in traditional medicine because of their non-addictive and non-toxic properties (61). Studies have demonstrated that naringin has antioxidant, anti-microbial, anti-mutagenic, anti-cancer, bone-protective, anti-inflammatory and cholesterol-lowering effects (62–65).
Chrysin
Chrysin, also known as poplar flavonoid, is 5,7-dihydroxyflavone. It is found in propolis, honey, passion fruit, mushrooms and other plant sources. Due to its multiple pharmacological (anticancer, antitumor, antidiabetic, antioxidant stress, antiinflammatory, anti-obesity, antiallergic, hepatoprotective, reproductive organ-protective, neuroprotective and cardioprotective) effects and low toxicity. Therefore, chrysin has potential medicinal value (66–76).
Pueraria
Puerarin is an isoflavone derived from dried root of the legume Pueraria lobata, known as wild kudzu or ‘Asian ginseng’ (77). It was first reported in Shennong Ben Cao Jing and has a long history of treating disease. Kudzu root contains abundant isoflavones, primarily soybean base and isoflavones and puerarin (78). Puerarin, has a structure similar to estradiol and has the molecular formula C21H20O9 and a relative molecular weight of 416; it was separated from Pueraria lobata in the late 1950s. Since then, its pharmacological properties have been extensively researched (68). It has been used to treat vascular disease, diabetes and its complications, cancer, bone-associated, Parkinson's and Alzheimer's disease, inflammation and alcohol-induced disease and exhibits antioxidant activity (79–88).
Use of flavinoids to prevent and treat osteoporosis at the cellular level and its signaling pathwayPhysiological bone remodelling process
Bone is in a constant state of remodeling, which is key for maintaining structure and function. Imbalances can lead to disease, such as osteoporosis. Numerous types of cell and cytokine, hormones and signaling pathway are involved in bone remodeling. Osteoblasts and osteoclasts are responsible for new bone formation and resorption, respectively (89–91).
Osteogenic effects of flavonoids on osteoblasts and associated signaling pathwaysBone morphogenetic protein (BMP)/Smads signalling pathway
BMPs are members of the transforming growth factor β superfamily and were first identified in 1960 (92). However, they were not isolated and purified until the late 1980s (93,94). To date, ~20 BMPs have been identified. BMP signaling is associated with bone formation (95,96). BMP is the initial inducer of osteoblastogenesis during bone development. It binds to type II BMP receptors to phosphorylate them; activated type II BMP receptors phosphorylate type I BMP receptors and bind to form complexes (97). The activated complex further activates the downstream BMP signaling protein receptor (R-Smad). Phosphorylated R-Smad binds to Smad4 and migrates to the nucleus, where it serves as a transcriptional enhancer and interacts with the transcription factors Runx2 and Osterix to affect the transcription of osteogenic-associated genes (98). Differentiation of bone precursor cells and initiation of osteoblast-specific factors (such as alkaline phosphatase) promote bone formation (99–101).
Quercetin has been shown to possess positive pharmacological effects on bone metabolism, such as preventing bone loss (43,102). Zhou et al (103) showed that 10 and 50 µM quercetin stimulates gene expression of the osteoblast markers, bone morphogenetic protein 2 (BMP-2), Runx2, osteopontin (OPN), osteocalcin (OCN), collagen type 1 (COL-1) and osterix in mouse adipose stem cells (mASCs) in vitro but does not affect proliferation. The osteogenic effect of quercetin at certain concentrations has not yet been determined (104). By contrast to Zhou, another study showed that quercetin enhances proliferation of bone marrow mesenchymal stem cells (BMSCs) on days one, four and seven after dosing in a dose-dependent manner with the greatest effect at a concentration of 2 µM. In the aforementioned study, quercetin enhanced alkaline phosphatase (ALP) activity and especially the middle and late markers (bone sialoprotein (BSP), BMP-2, OPN and OCN) in a dose-dependent manner, with the greatest stimulation occurring at 2 µM. Furthermore, quercetin not only promoted osteogenic differentiation of BMSCs, but also promoted secretion of angiogenic factors in a dose-dependent manner, with the most significant effect at a concentration of 2 µM (103). Liu et al (105) found that naringin addition had a bidirectional effect on the cell proliferation and ALP activity of human amniotic fluid-derived stem cells (hAFSCs). At a concentration of 200 µg/ml, naringin inhibited the growth and moderately increased the ALP activity of hAFSCs; while at lower concentrations (1–100 µg/ml), naringin significantly enhanced the proliferative capacity and ALP activity of hAFSCs in a dose-dependent manner. In addition, naringin promotes osteogenic differentiation of hAFSCs via BMP signalling pathways; this finding, however, has only been assessed in vitro. Menon et al (106) showed that chrysin released from a chitosa/carboxymethyl cellulose/nanohydroxyapatite stent stimulates proliferation of mouse mesenchymal stem cells (mMSCs) and promotes osteoblast differentiation; this may be due to upregulation of Runx2 and downregulation of Runx2 co-repressors.
Wnt/β-catenin signalling pathway
The Wnt/β-catenin signalling pathway activates transcription of Wnt gene in the nucleus via β-catenin (107). When the extraneous osteoblast Wnt factor binds to the membrane receptor frizzled, a series of membrane and cytoplasmic protein interactions lead to dimer formation. This results in β-catenin accumulation in the cytoplasm and subsequent entry into the nucleus (108). T cell/lymph enhancement factors combine to form a complex, which activates transcription of downstream target genes and promotes differentiation and proliferation of osteoblasts (109).
Lin et al (110) demonstrated that naringin promotes osteoblast formation via activation of osteogenic genes such as forkhead box protein C2 (Foxc2), core binding factor α1 (Cbα1) and OCN in in vitro osteogenic differentiation of BMSCs while decreasing peroxisome proliferator-activated receptor γ2 (PPARγ2) and upregulating Foxc2 expression partly via the Indian hedgehog signaling pathway. This revealed the mechanism by which naringin promotes osteogenesis of bone marrow MSCs. However, no in vivo animal experiments were performed to verify this. Liu et al (105) revealed that naringin may promote osteogenic differentiation of hAFSCs via the Wnt/β-catenin signaling pathway.
MAPK signalling pathway
The MAPK signaling pathway is key for regulation of osteoblast proliferation and differentiation. MAPKs are a group of serine/threonine kinases that serve key signaling transducer roles in translating extracellular stimuli into cellular responses (111). Activation of the MAPK cascade occurs via sequential phosphorylation of three protein kinases. Upon stimulus, MAPKK kinases (MAPKKKs) is activated, phosphorylating MAPK kinases (MAPKKs), which then phosphorylates MAPK (112). Certain studies have suggested that there are three primary pathways involved in MAPK signaling: Extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathway; different pathways receive different stimuli and serve different roles (113,114).
Zhou et al (103) reported that quercetin activates the ERK and p38 signaling pathways but not the JNK signaling pathway. Wu et al (115) demonstrated that the optimal concentration of ICA to promote osteogenic differentiation of bone marrow MSCs is 20 µM and ERK, p38 and JNK MAPK signaling pathways are involved in this process. Liu et al (116) discovered that hesperetin relieves glucocorticoid-induced osteogenic differentiation of BMSCs via the ERK signaling pathway. Nonetheless, the aforementioned study has certain limitations. First, bone marrow MSCs and glucocorticoid-induced osteoporosis (GIOP) osteogenic differentiation involve multiple signaling pathways. This experiment only investigated the ERK signaling pathway and whether other signaling pathways are involved in this process remains unclear. To the best of our knowledge, there is only one in vitro study and the effect of hesperetin on GIOP in vivo is still ambiguous. Xue et al (117) revealed that hesperetin promotes osteogenic differentiation of hBMSCs in vitro, potentially via ERK and Smad signaling pathways. The aforementioned study has limitations. First, only a low concentration (1 µM) of hesperetin was used to investigate the effect of hBMSC osteogenic differentiation and its underlying mechanism. Therefore, the effect of different concentrations of hesperetin on osteogenic differentiation of hMSCs and its mechanism needs to be further studied. Secondly, both ERK and Smad1/5/8 signaling pathways are involved in hesperetin-induced MSC osteogenic differentiation and it is unknown whether there is crosstalk between the ERK and Smad1/5/8 pathways. Yang et al (118) suggested that activation of ERK1/2 and p38 MAPK signaling pathways is involved in Puerarin-mediated osteogenesis and that the ERK1/2 signaling pathway plays a more significant role than the p38 signaling pathway in the induction of osteogenic phenotypic differentiation of BMSCs by puerarin.
PI3K/AKT signaling pathway
The PI3K/AKT signaling pathway is widely present in cells (119). PI3K family members are proto-oncogenes and key kinases of inositol and phosphatidylinositol (120). AKT is a serine/threonine-protein kinase and downstream target kinase in the PI3K signal transduction pathway (121). The PI3K/AKT signaling pathway regulates proliferation, differentiation and apoptosis of osteoblasts and osteoclasts (122,123).
Zhai et al (124) revealed that ICA promotes osteogenesis of BMSCs via the PI3K/AKT/endothelial NO synthase (eNOS)/NO/cyclic guanosine monophosphate (cGMP)-protein kinase-G (PKG) signaling pathway. However, the mechanism underlying PI3K activation by ICA should be further investigated. Lv et al (125) demonstrated that Puerarin at concentrations <10 µM stimulates proliferation and osteogenic differentiation of bone marrow MSCs in a dose-dependent manner. The estrogen receptor mediates this effect via the NO/cGMP/PKG II signaling pathway. However, higher concentrations of Puerarin impairs proliferation and differentiation of osteoblasts. Zhang et al (126) showed that Puerarin significantly inhibits lipopolysaccharide (LPS)-induced osteoclast differentiation in osteoclast precursor RAW264.7 cells. LPS stimulates activation of AKT in osteoclast precursor RAW264.7 cells, while puerarin inhibits activation of AKT.
Inhibitory effect of flavonoids on osteoclasts and associated signaling pathways
Osteoprotegerin (OPG)/nuclear factor-κB (RANK)/RANK ligand (RANKL) signalling pathway. In 1997, the OPG/RANK/RANKL signaling pathway was discovered by Simonet et al (127) and investigated in areas such as orthopedic disease. RANK is the only known RANKL receptor activator that binds to the C-terminus of RANKL to initiate intracellular signaling events and promote activation and maturation of osteoclasts (128–130). OPG competitively binds to RANKL and inhibits the RANK/RANKL signaling pathway. This antagonizes RANKL to promote osteoclast differentiation and osteoblast function and or activates RANKL to inhibit osteoclast differentiation (131,132). RANKL/OPG ratio regulates RANKL-mediated signaling. A high RANKL/OPG ratio increases osteoclast differentiation (127,133). Low RANKL/OPG ratio negatively regulates osteoclast differentiation in mature osteoclasts. Therefore, OPG/RANKL/RANK is a key mechanism regulating the coupled balance of osteoclast formation and differentiation and bone remodeling (134).
Yuan et al (135) suggested that Puerarin has a time–dependent promoting effect on expression of OPG mRNA in MC3T3-E1 cells and inhibits expression of RANKL mRNA. Shan et al (136) demonstrated that Puerarin at 20 µM promotes proliferation of MC3T3-E1 cells. Moreover, Puerarin promotes MC3T3-E1 cell differentiation at certain concentrations and positively affect osteogenic differentiation by directly targeting RANKL-induced upregulation of microRNA-106b (Table I).
Animal studies on use of flavonoids to prevent osteoporosis
The primary types of osteoporosis are postmenopausal, disuse and GIOP (137). Huo et al (138) revealed that chrysin upregulates expression of osteogenic proteins (ALP, COL-1, Runx2 and OCN) both in vivo and in vitro and that induced osteogenic differentiation of dental pulp stem cells (DPSCs) relies on activation of the Smad3 pathway. Furthermore, mineralized bone tissue formation is induced in DPSCs in vivo in an ectopic osteogenesis model in nude mice and a rat cranial defect model. However, the mechanism by which chrysin increases Smad3 expression and activation requires further investigation. Liu et al (139) showed that the combined application of Puerarin and zinc promotes serum levels of OCN and ALP expression in ovariectomy (OVX) rats and inhibits serum levels adiponectin and adiposity in bone marrow. Co-administration of Puerarin (low dose) and zinc partially reverses OVX-induced bone loss in rats and inhibits osteoporosis, suggesting the potential use of Puerarin and zinc in treating osteoporosis. Huang et al (140) suggested that ICA promotes fracture healing in OVX mice in vivo and induces bone formation and inhibits adipogenesis in BMSCs; these bone-promoting and anti-adipogenic effects are mediated by the Wnt signaling pathway. Using OVX mice in vivo to simulate osteoporosis, Wang et al (141) found that naringin treatment improves bone strength by activating the Wnt/β-Catenin signaling pathway. Xue et al (117) used a rat osteotomy model to confirm that hBMSCs combined with hesperetin/gelatin sponge scaffolds accelerates fracture healing in vivo. Yuan et al (135) verified that Puerarin effectively prevents bone loss in OVX mice. The anti-osteoporotic activity of Puerarin may be associated with its effect on osteoclast formation and RANKL OPG expression in osteoblasts. Zhang et al (126) revealed that Puerarin attenuates LPS-induced bone loss in a mouse cranial osteolysis model (Table II).
Prospects
Osteoporosis is a global public health issue and is considered the second most common health problem after coronary heart disease by the WHO. Current approaches toward osteoporosis prevention and treatment focus on drug therapy including bisphosphonates, calcitonin and SERMs. However, because these drugs have side effects, such as increased risk of cardiovascular events, breast cancer and venous thromboembolism, researchers have turned to traditional Chinese medicine (142,143).
Traditional Chinese medicine has developed over thousands of years based on a different perspective from Western medical knowledge. The natural abundance flavonoids, low price, high osteogenesis rate and low immune rejection during clinical treatment have made the application of flavonoids in bone tissue engineering research more widespread. However, current investigations have certain limitations. First, most research on flavonoids remains at the cellular level and research at the animal level needs to be more extensive. Additionally, the pharmacological effect of flavonoids is a complex process that involves multiple systems. Although certain mechanisms have been elucidated, further research is needed. In addition to the aforementioned signalling pathways, there are other overlapping signalling pathways that interact with each other. Current research has limitations, such as focusing on only independent pathways and molecular targets and there are few clinical studies (50).
More in-depth research on flavonoids is needed to develop effective and inexpensive novel drugs for clinical applications.
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Authors' contributions
LC wrote the manuscript. FT, JW and YZ edited the manuscript. CW revised the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.
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Competing interests
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Chemical structure of six flavonoids.
Use of flavonoids in the prevention and treatment of osteoporosis at the cellular level.
Flavonoid
First author, year
Cell type
Effect
(Refs.)
Quercetin
Sharan, 2014
hAFSCs
Increased BMP-2, Runx2, OPN, OCN, COL-1 and Osx expression