Vascular endothelial growth factor (VEGF) is the most potent proangiogenic factor. EPO, a glycoprotein, is considered as the principal stimulator for erythropoiesis primarily. The expression of HIF-1α is induced by a hypoxic environment, and it subsequently upregulates downstream key factors, such as EPO and VEGF, which promote angiogenesis to adapt to the environment and recover the oxygen content.

The primary cause of the ectopic overexpression of VEGF in tumors is the dysregulated expression of HIF-1α involving the c-X-c chemokine receptor type 4 (CXCR4)/stromal-derived cell factor-1 (SDF-1) axis (19). The study by Li et al (20) conducted on cerebral ischemic rats, found that HIF-1α attenuated neuronal apoptosis, partially by upregulating EPO expression. There is a novel molecular mechanism for the anti-angiogenic effects of peroxisome proliferator-activated receptor α, which are achieved by inhibiting ischemia-induced EPC mobilization and homing through the inhibition of the HIF-1α/SDF-1 pathway (21). Rankin et al (22) found that osterix-VHL mice with a deficiency in VHL in osteoblasts exhibited overexpressed HIFs, accompanied by a significant increase in circulating red blood cells. Gerri et al (23) reported that HIF-1α regulated hematopoietic stem cells upstream of the Notch signaling pathway.

HIF-1α, in response to hypoxic irritation, participates in the regulation of glucose transporters and glycolytic enzymes, which are key genes in energy metabolism and exert critical effects on cell survival (24). Moreover, HIF-1α inhibits pyruvate dehydrogenase by activating pyruvate dehydrogenase kinase 1 (PDK1), and thereby, pyruvate is redirected from the tricarboxylic acid (TCA) cycle and converted into lactate (25).

The overexpression of constitutive cardiac-specific HIF-1α leads to changes in cellular metabolism and increased glucose utilization, subsequently resulting in cardiomyopathy in aging mice (26). On the other hand, the deletion of HIF-1α in cardiomyocytes results in decreased ATP, lactate and phosphocreatine levels, and inn an impaired myocardial contractility (27). Chondrocytes maintain an optimal energy balance during endochondral ossification, which is achieved by confined HIF-1α signaling (28). However, it is only under hypoxic conditions that glucose uptake and bone resorption can be affected by HIF-1α knockdown. HIF-1α promotes glycolysis during hypoxia; however, it also affects metabolism under normoxic conditions. A decreased HIF-1α activity also has effects on mitochondrial metabolism that results in mitochondrial loss and lipid accumulation, along with reduced oxidative phosphorylation and fatty acid metabolism (26,29). In addition, studies have demonstrated that HIF-dependent metabolic processes can also modulated by dimethyloxalylglycine, desferrioxamine, prolyl hydroxylase (PHD) and other small molecules (30,31).

HIF-1α is an endogenous anti-oxidative stress modulator. The oxidative stress pathway induces the activation of HIF-1α, and increases the production of mitochondrial complex II-mediated reactive oxygen species (ROS) (32,33). Moreover, it has been demonstrated that increased superoxide anion radicals induce PHD inactivation, resulting in the stabilization and accumulation of HIF-1α (34). Under hypoxic conditions, HIF-1α dynamically regulates glucose flux through the glycolytic pathway to resist the increased risk of ROS production and confers protection against apoptosis and renal injury in diabetes (35,36).

In recent years, increasing evidence has indicated that HIF-1α can enhance antioxidant activity and neuroprotection (37,38). HIF-1α has the ability to mitigate this toxicity or regulate redox homeostasis by limiting TCA activity, regulating the levels of NADPH and glutathione (GSH), and reducing mitochondrial mass through the upregulation of the mitochondrial proteins, PDK1 and Bcl-2 interacting protein 3 (BNIP3) (39). Furthermore, HIF-1α may be an indirect player in the promotion of mitochondrial-selective autophagy and may subsequently lower the mitochondrial mass, which inhibits the oxidation of both glucose and fatty acids, and reduces mitochondrial ROS production under hypoxic conditions (40). A previous study revealed that HIF-1α can activate the nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway to protect against ischemia-reperfusion cardiac and skeletal muscle injuries (41).

Previous research has indicated that HIF-1α may affect the osteogenesis of osteoblasts through the prevention of chondrocyte cell death in the growth plate, and also via direct or indirect actions on the delivery of oxygen and nutrients, together with metabolic adaptations (8). It has been reported that the overexpression of HIF-1α, through its downstream marker, BNIP3, reduces the inhibitory effects of dexamethasone on hypoxia-induced mitophagy and protects osteocytes from apoptosis (42). There is also evidence to suggest that miRNA-21, by upregulating the activation of HIF-1α and p-Akt, can promote the osteogenic ability of bone MSCs (BMSCs) (43). HIF-1α does not only promote osteogenesis, but also has repairing effects on bone (44). Moreover, it has been demonstrated that prolonged HIF-1α signaling in chondrocytes, interfering with cellular bioenergetics and biosynthesis, results in skeletal dysplasia by collagen overmodification (27).

The delicate balance between osteoblastic bone formation and osteoclastic bone resorption is a key factor in the regulation of mature bone tissue formation (45). Nevertheless, no consensus has yet been reached on the role of HIF-1α in regulating osteoclast differentiation, at least to the best of our knowledge.

HIF-1α expression has been proposed to increase bone erosion in rheumatoid arthritis (46). HIF-1α is involved in the increase of osteoclastogenesis and bone resorption, since it has recently been shown to enhance the osteoclast-mediated stimulation of BMSC differentiation by secreting cardiotrophin-1 (47). Moreover, HIF-1α functions by activating the JAK2/STAT3 pathway, promoting the expression of RANKL, and thus enhancing the differentiation of osteocyte-mediated osteoclastic in vitro (48). HIF-1α also plays a pro-apoptotic role in JNK/caspase-3 signaling pathway activation. Osteocyte-mediated osteoclastogenesis has been shown to be reduced with a concomitant decrease in HIF-1α and caspase-3 expression (49). A previous study demonstrated that the deceleration of osteoclastogenesis occurred under conditions of HIF-1α deficiency, by inhibiting AMPK signaling under anoxic conditions (50). Of note, HIF-1α knockdown reduces bone resorption under both normoxic and hypoxic conditions. Thus, the targeting of HIF-1α may prove to be of value in th treatment of osteoporosis (13).

Both the VHL/HIF and PHD/HIF signaling pathways in osteoblasts have been shown to reduce osteoclastogenesis by increasing osteoprotegerin expression and inhibiting sclerostin expression, resulting in increased bone formation and decreased resorption (14,51). In addition, it has been suggested that the activation of osteoblast HIF-1α contributes to the inhibition of osteoclastogenesis, by increasing IL-33 expression (52).

A vital role in bone remodeling and vascularization is attributed to the HIF-1α/VEGF signaling pathway (53). The study by Kusumbe et al (54) demonstrated endothelial HIF-1α as a critical promoter of type H vessel formation in the metaphysis. HIF-1α has also been implicated in the increased number of type-H vessels and the restoration of bone mass (55–57). The miR-497B195 cluster has been proposed to regulate angiogenesis during coupling with osteogenesis, by maintaining endothelial Notch and HIF-1α activity (58). Furthermore, HIF-1α may have a dual function in the regulation of osteogenesis-angiogenesis coupling of long bone via the ROS-HIF1α/p53 axis (59).

HIF-1α has also been demonstrated to trigger wound healing and functional recovery by regulating corresponding stem cells (60,61). BMSCs, a class of heterogeneous cells, have a series of feasible and diverse clinical values for generating stroma which can support hematopoiesis, bones, adipocytes and cartilage (62).

HIF-1α regulates the expression levels of surface molecules, such as SDF-1, a downstream gene of HIF-1α, which binds to its specific receptor, CXCR4, forming a pair of coupling molecules and promoting stem cell migration to ischemic and hypoxic sites (63). Guo et al (62) demonstrated that the HIF-1α/SDF-1/CXCR4 axis enhanced BMSC migration, and alleviated neuronal damage and apoptosis. Moreover, there is evidence to suggest that the increased secretion of HIF-1α induced by the hypoxic conditions of surrounding brain tissue accelerates the fracture repair process via chemotaxis due to the SDF-1/CXCR4 axis. In addition, the silencing of HIF-1α has been shown to decrease MSC migration, as well as the mRNA and protein levels of SDF-1 and CXCR4 in MSCs (64).

HIF-1α is a vital factor in iron metabolism by regulating the expression of iron-related proteins, such as divalent metal transporter 1, ferroportin 1, duodenal cytochrome B and TFR (65,66). An overload of iron has been found to be related to the dysfunction of MSCs and to the damage of the microenvironment that may be involved in the pathogenesis of myelodysplastic syndromes, and which may be achieved by the regulation of cytokine of MSCs through the ROS/HIF-1α pathway (67). It has been demonstrated that HIF-1α induces TFR1 expression, thereby increasing iron uptake (68). In addition, it has been suggested that HO-1, induced by HIF-1α, degrades heme into biliverdin, carbon monoxide and iron (69). Weinreb et al (70) and Guo et al (71) demonstrated that in various brain regions of adult mice, the upregulation of HIF-1α by the iron chelator, M30, results in differentially induced levels of TFR, tyrosine hydroxylase and EPO (72).

Ferroptosis is a new form of regulated cell death as a result of iron-dependent lipid peroxidation (73). Moreover, HIF-1α downregulation also promotes ferroptosis by inducing ferritin heavy chain degradation in RANKL-stimulated bone marrow-derived macrophages. A previous in vitro study demonstrated that the overexpression of inhibitor of apoptosis-stimulating protein of p53 inhibited ferroptosis through the Nrf2/HIF-1α/TF signaling pathway (74). In another study, following pre-treatment with roxadustat (an inhibitor of HIF prolyl hydroxylase), the risk of ferroptosis was correspondingly reduced, along with increased levels of antioxidant enzymes and GSH, and decreased iron accumulation (75).