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

Figure 1

The effects of the HIF pathway on mesenchymal stem cells (MSCs). HIF-1𝛼 increases the proliferation of MSCs through the enhancement of TWIST expression, which downregulates the E2A-p21 pathway. The HIF pathway promotes the SDF-1𝛼 - and VEGF-dependent migration of MSCs by increasing the expression of the chemokine receptors CXCR4 and VEGFR1. HIFs inhibit the osteogenic and adipogenic differentiation of MSCs by decreasing the expression of RUNX2 and PPAR-𝛾2. HIFs enable MSCs to survive by activating G6PT to increase their metabolic flexibility. In summary, HIFs promote the proliferation, migration, and survival of MSCs but inhibit the osteogenic and adipogenic differentiation of MSCs.