HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

“…Inefficient resorption of the matrix could be caused by osteoclastic alterations or, alternatively, by anomalous modifications of the matrix rendering it more resistant to degradation. The latter could result, for instance, from alterations in the biosynthesis of collagens in chondrocytes and osteolineage cells, as HIF signaling is known to improve the efficiency of posttranslational hydroxylation of collagens and collagen crosslinking, thereby determining the conformational stability of collagen triple helices (10,36,37). The low bone turnover state at adult ages in Vhl-deficient mice indicates that increased bone matrix deposition and mineralization must have occurred at earlier stages in life, similar to the findings made upon Ocn-Cre-driven Vhl inactivation, targeting mature osteoblasts (11).…”

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

“…Hif1α was shown to promote the expression of Sox9 and to elevate the expression of glycolytic enzymes and glucose transporters to allow chondrocyte differentiation and adaptation to hypoxic conditions (Pfander et al, 2003;Amarilio et al, 2007). Hif1α was also shown to upregulate VEGFA expression in the growth plate (Schipani et al, 2001;Zelzer et al, 2004) as well as promote collagen hydroxylation to enable collagen secretion by hypoxic chondrocytes (Bentovim et al, 2012).…”

Blood vessel formation and function in bone

“…HIF target genes are involved in a variety of biological processes, such as anaerobic metabolism and angiogenesis. Remarkably, chondrocytes survive in hypoxic conditions by utilizing an anaerobic metabolism, and HIF1α regulates a number of metabolic genes that play a vital role in this process (Bentovim et al, 2012;Dunwoodie, 2009). Accordingly, the conditional deletion of Hif1a in mice causes massive cell death in the inner hypoxic zone of the growth plate (Schipani et al, 2001).…”

“…Conversely, the osteoblast-specific overexpression of HIF1α or loss of VHL results in increased bone angiogenesis and osteogenesis (Wang et al, 2007). HIF1α and HIF2α also transcriptionally regulate the expression of ECM genes, and their absence affects chondrogenesis and osteogenesis owing to impaired ECM secretion (Bentovim et al, 2012;Saito et al, 2010;Yang et al, 2010). The activation of hypoxia signaling in ECs also causes an increase in type H capillaries, as well as enhanced endochondral angiogenesis and osteogenesis .…”