HIF‐1α plays an essential role in BMP9‐mediated osteoblast differentiation through the induction of a glycolytic enzyme, PDK1

Abstract

Bone homeostasis is regulated by bone morphogenic proteins (BMPs), among which BMP9 is one of the most osteogenic. Here, we have found that BMP9 rapidly increases the protein expression of hypoxia-inducible factor-1α (HIF-1α) in osteoblasts under normoxic conditions more efficiently than BMP2 or BMP4. A combination of BMP9 and hypoxia further increased HIF-1α protein expression.HIF-1α protein induction by BMP9 is not accompanied by messenger RNA (mRNA) increase and is inhibited by the activation of prolyl hydroxylase domain (PHD)containing protein, indicating that BMP9 induces HIF-1α protein expression by inhibiting PHD-mediated protein degradation. BMP9-induced HIF-1α protein increase was abrogated by inhibitors of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) kinase, indicating that it is mediated by PI3K-AKT signaling pathway. BMP9 increased mRNA expression of pyruvate dehydrogenase kinase 1 (PDK1), a glycolytic enzyme, and vascular endothelial growth factor-A (VEGF-A), an angiogenic factor, in osteoblasts. Notably, BMP9-induced mRNA expression of PDK1, but not that of VEGF-A, was significantly inhibited by small interference RNA-mediated knockdown of Hif-1α. BMP9-induced matrix mineralization and osteogenic marker gene expressions were significantly inhibited by chemical inhibition and gene knockdown of either Hif-1α or Pdk-1, respectively. Since increased glycolysis is an essential feature of differentiated osteoblasts, our findings indicate that HIF-1α expression is important in BMP9-mediated osteoblast differentiation through the induction of PDK1.

Hydrogel scaffolds in bone regeneration: Their promising roles in angiogenesis

“…Indeed, M1 macrophages secret VEGF and are involved in the initiation of angiogenesis; whereas M2 are responsible for the later stages of angiogenesis, stabilizing the vasculature, and typically secreting PDGF-BB. Consistent with in vitro results, the MSC-encapsulated (2022) showed that incorporating TGF-β1 into Li-based hydrogel promotes both osteogenesis and angiogenesis, in which TGF-β1 guides macrophage polarization toward the M2 phenotype and Li ions enhance osteogenesis. Figure 4 represents how a hydrogel-based scaffold enhances angiogenesis by modulating macrophage phenotype.…”

“…They reported that the constructed scaffolds supported osteoblast proliferation and osteogenesis and promoted tubule formation. Recently, Amir et al (2022) indicated that HIF-1α plays an indispensable role in BMP-9-mediated preosteoblasts differentiation into osteoblasts and vascularization, whereas HIF-1α knockdown or inhibition significantly suppressed the expression of osteogenic markers and matrix mineralization in a BMP-9-dependent manner. In another study, Guo et al (2020) revealed that the protective activity of salidroside on bone loss is related to its stimulatory effects on angiogenesis-osteogenesis coupling via regulating the HIF-1α/VEGF axis.…”

Versatile Hypoxic Extracellular Vesicles Laden in an Injectable and Bioactive Hydrogel for Accelerated Bone Regeneration

“…As shown in Figure 9D, the KEGG enrichment results showed that the differentially expressed proteins in Hypo‐EVs were highly correlated with Hif‐1, PI3K/AKT, and ECM‐receptor interaction signaling pathways, which are known to be involved in the process of osteogenic differentiation. [ 33b,c,45 ]…”

Research Status of HIF-1α at Cartilage Level

“…Amir M S et al found that in bone homeostasis regulated by bone morphogenetic protein (BMP), BMP9 inhibited PHD-mediated protein degradation under normal conditions and increased osteoblasts protein expression of HIF-1α. This finding means that BMP9 can effectively increase the expression of the HIF-1α protein in combination with hypoxic conditions [12].…”