The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

Figure 2

Model of the role of the HIF pathway in angiogenic-osteogenic coupling. Under hypoxia, resident cells, especially osteoblasts, sense the reduced oxygen tension via the HIF pathway; the HIF pathway is activated, leading to the upregulation of HIF-𝛼 and its target genes, especially VEGF. Moreover, the HIF pathway can also be activated by PHD inhibitors, siRNA against PHD, and VHL gene knockout. The accumulation of HIF-𝛼 and VEGF promotes bone regeneration in two ways. One way is that VEGF stimulates new blood vessel growth into bone, bringing osteogenic signals and more osteoblast progenitors, which mature and form new bone. The other is that HIF-𝛼 and VEGF function in an autocrine or paracrine mode to directly promote the chemotaxis of osteoblast progenitors and induce osteogenic differentiation, migration, and proliferation, accelerating bone mineralisation.