Hypoxia-inducible factors (HIFs) are transcriptional activator complexes that perform a central role in the expression of oxygen-regulated genes. These genes are involved in the proliferation and apoptosis of cells, angiogenesis, erythropoiesis, energy metabolism, vasomotor function, and so on ^[1][2][15,16]. Thus, HIFs are essential for normal growth and development and also participate in the pathological processes, including tumor progression and tissue regeneration ^[3][17]. Heterodimeric transcription factors (HIFs) complex are composed of α-subunits (HIF-1α, HIF-2α, and HIF-3α) and the β-subunit (HIF-1β)/aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-1β/ARNT is expressed stably in cells, whereas HIF-αs are degraded under the condition of normal oxygen bioavailability and accumulate rapidly in a hypoxic environment. HIF-1α, HIF-2α, and HIF-3α bind to HIF-1β to form HIF-1, HIF-2, and HIF-3, respectively. Thus, the stability of the HIF-1α subunit seems to determine HIF-1 formation. Similarly, the formation of HIF-2 is mainly determined by the abundance of the HIF-2α subunit.

In mammalian cells, three HIF-α subunit isoforms (HIF-1α, HIF-2α, and HIF-3α) are encoded by three HIF-α genes: HIF1A, HIF2A, and HIF3A, respectively. When oxygen concentration drops to <5%, HIF-1α is stably expressed, enters the nucleus, dimerizes with HIF-1β, and binds to HIF-response elements (HRE) of targeted gene promoters ^[2][16]. When oxygen is abundant in cells (>5%), the Prolyl-4-hydroxylases (PHDs) bind to HIF-1α and hydroxylate the proline residues, which leads to the recruitment of the Von Hippel-Landau (VHL) tumor suppressor E3 ligase complex. Eventually, the proteasomal is poly-ubiquitylated and degraded ^[4][18]. In addition, factor inhibiting HIF (FIH) also restricts the binding of HIF-αs to transcriptional co-activators CBP/p300 through hydroxylating (N-terminal) asparaginyl residues when oxygen is abundant ^[5][19]. HIF-2α is regulated by oxygen in a similar manner to HIF-1α. In addition to intracellular oxygen tension, several growth factors can also regulate HIF-α subunits in a hypoxia-independent way ^[6][20]. HIF-1 has been studied more extensively than HIF-2, and HIF-1 and HIF-2 have overlapping and unique biological functions. It is reported that HIF-1α responds to acute hypoxia mainly, whereas HIF-2α is the prime subunit that responded to chronic exposure to low oxygen at high altitudes ^[7][21]. HIF-1α is generally expressed in cells and regulates downstream genes, including VEGF, GLUT-1, AK-3, ALD-A, PGK-1, PFK-L, and LDH-A through binding to HRE to regulate many metabolic enzymes ^[8][22] (Maxwell, 1999). The role of HIF-1 in promoting angiogenesis also benefits cancer development. HIF-2 regulates erythropoiesis and vascularization and is essential for embryonic development ^[4][18]. In addition, HIF-2 is also involved in the progression and metastasis of solid tumors ^[9][23]. Another HIF-α protein, HIF-3α, can bind to ARNTs to restrain HIF-1α- or HIF-2α-mediated transcription, but its transcriptional capacity is weaker than other HIFs ^[2][10][16,24]. HIF-3α is relatively unknown in terms of regulating the hypoxia response, and many studies have shown that HIF-3α may play a dual part as a hypoxia-inducible transcription factor in recent years ^[11][25]. The determination of genome-wide binding of the human HIF-3 and its role requires extensive scientific research (Figure 1).

More recent studies have demonstrated the role of 最近的研究表明HIF-1 in bone growth and repair. Ref. ^[12] used spongy scaffolds that contained dimethyloxalylglycine (在骨骼生长和修复中的作用。参考文献[26]使用大鼠颅骨缺陷中含有二甲基噁酰甘氨酸（DMOG) in rat calvarial defects to imitate hypoxia to up-regulate ）的海绵支架来模仿缺氧以上调HIF-1α, and found that angiogenesis was accelerated and bone regeneration was enhanced. Ref. ^[13] found that ，发现血管生成加速，骨再生增强。参考文献[27]发现HIF-1α could facilitate osseointegration of tissue-engineered bone, dental implants, and new bone formation around implants, which was verified in a canine model. Another study has shown that expression of gingival HIF-可以促进组织工程骨，牙科植入物和植入物周围的新骨形成的骨整合，这在犬类模型中得到了验证。另一项研究表明，皮下注射1α protein in mice was apparently increased, and the ability of bone regeneration was enhanced at the onset of periodontitis resolution, after subcutaneous injection of 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1, ，4-二氢苯甲醚-4-酮-3-羧酸（1，4-DPCA/hydrogel), a hydrogel-formulated PHD inhibitor ^[14]. Gene ablation of 水凝胶），一种水凝胶配方的PHD抑制剂，小鼠牙龈HIF-1α蛋白的表达明显增加，并且在牙周炎消退开始时骨再生能力增强[28]。软骨细胞中phd2 in chondrocytes promotes endochondral osteogenesis through up-regulation of 的基因消融通过HIF-1α signaling, resulting in a significant growth of long bones and vertebrae ^[15]. In the process of bone regeneration, 信号传导的上调促进软骨内骨成骨，导致长骨和椎骨的显着生长[29]。在骨再生过程中，HIF-1α not only promotes angiogenesis but also regulates metabolic adaptations by inducing glycolysis transformation to promote cell survival ^[16]. Hence, 不仅促进血管生成，还通过诱导糖酵解转化来调节代谢适应，以促进细胞存活[30]。因此，HIF-1 serves an indispensable role in osteogenesis and bone restoration ^[12][17]. When osteoblasts and other associated cells sense reduced oxygen tension, intracellular 在成骨和骨骼修复中起着不可或缺的作用[26，31]。当成骨细胞和其他相关细胞感觉到氧张力降低时，细胞内HIF-1α is stably expressed to regulate the expression of the angiogenic and osteogenic genes ^[18]. Additionally, the mechanisms by which 稳定表达以调节血管生成和成骨基因的表达[32]。此外，HIF-1 regulates downstream genes to promote osteogenesis and bone repair are quite complex. The role of 调节下游基因以促进成骨和骨修复的机制相当复杂。HIF-1 in mediating downstream signaling to regulate bone mass in different animal models or cells is displayed in Table 在介导下游信号以调节不同动物模型或细胞中的骨量中的作用如表1.所示。