Runx2 Protein Stabilizes Hypoxia-inducible Factor-1α through Competition with von Hippel-Lindau Protein (pVHL) and Stimulates Angiogenesis in Growth Plate Hypertrophic Chondrocytes

Abstract

Background: Runt-related transcription factor 2 (Runx2) is a key factor in bone development. Hypoxia-inducible factor-1␣ (HIF-1␣) is the primary regulator of blood vessel formation. Results: Runx2 bound and activated HIF-1␣ by competing with von Hippel-Lindau protein (pVHL), protecting HIF-1␣ from degradation. Conclusion: Runx2 stabilizes HIF-1␣ during endochondral bone formation. Significance: Runx2/HIF-1␣ stimulate the invasion of blood vessels in hypertrophic zones.

NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2

“…However, how Runx2 downregulates IKKb is an open question. Given that Runx2 is a transcription factor, we can speculate that Runx2 promotes the expression of IKKb-degrading proteins such as Keap1 or that it acts as a repressor of the IKKb gene 32 .…”

Hypoxia-inducible Factor 1α Regulates a SOCS3-STAT3-Adiponectin Signal Transduction Pathway in Adipocytes

“…Following hydroxylation, HIF1␣ is ubiquitinated by the E3 ubiquitin ligase von Hippel-Lindau tumor suppressor and degraded via the proteasome pathway. Under hypoxia, prolyl hydroxylases are inactive due to lack of substrate, and HIF1␣ is no longer subjected to hydroxylation and degradation and can then bind to ARNT and activate transcription of HIF target genes (17)(18)(19).…”

Hypoxia and Pulmonary Hypertension

“…MiR-204 is involved in the activation of the nuclear factor of activated T cell (NFAT) pathway, the Rho pathway, VSMC proliferation and resistance to apoptosis, as well as downregulation of transcripts such as bone morphogenetic protein receptor type II (BMPR2) and interleukin-6 (IL-6) [60][61][62]. Also, miR-204 regulates the expression of the Runt-related transcription factor 2 (RUNX2), which has been shown to stabilise HIF-1α in chondrocytes by competing with VHL [20,63]. In the context of hypoxia, RUNX2 is upregulated, since miR-204 is downregulated, and therefore sustains HIF-1α activation, which in turn contributes to aberrant VSMC proliferation, resistance to apoptosis and their transdiferentiation to osteoblast-like cells [20].…”