Hypoxia-inducible factor-1α restricts the anabolic actions of parathyroid hormone

Abstract

The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1α in osteoanabolic signaling, we assessed the effect of Hif-1α loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1α in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1α protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1α-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1α functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1α function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

Direct or indirect stimulation of adenosine A 2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2

“…As dipyridamole blocks purine transport into cells via ent1, it is possible that hypoxic transcriptional regulation of adenosine transporters may modulate adenosine regulated bone formation. It has been reported that osteoblast function and bone formation are strongly oxygen dependent (45), and HIF regulates osteoclast-mediated bone resorption and enhances osteoclast differentiation (46) and limits the anabolic effect of parathyroid hormone (47). A2AR expression and function is also regulated by, most notably, inflammatory stimuli (48,49).…”

Obstructive Sleep Apnea and Metabolic Bone Disease: Insights Into the Relationship Between Bone and Sleep

“…HIF-1a directly stimulates osteoclast activity, (72) directly inhibits mesenchymal stem cell (MSC) osteogenic and adipogenic differentiation (71) and blocks the osteoanabolic effects of PTH in mature mouse bone. (73) HIF-1a also induces production of vascular endothelial growth factor (VEGF). In humans, VEGF stimulates MSCs, their osteogenic differentiation, and the subsequent proliferation and survival of osteoblasts.…”

Gene profile of soluble growth factors involved in angiogenesis, in an adipose‐derived stromal cell/endothelial cell co‐culture, 3D gel model

“…BMP‐7 is involved in improvement of recovery after ischemic insult, promoted endothelial cell survival and induced angiogenesis indirectly by increasing VEGF expression , while a BMP‐7 variant (BMP‐7v) has been shown to inhibit angiogenic endothelial cord formation in glioblastoma multiforme . In ASCs, a recent study has shown that angiogenic genes ( VE‐cadherin , VEGFA and HIF‐1 α) were suppressed when treated with noggin or dorsomorphin, and as a result weakened angiogenesis . In our investigation, ASC co‐culture promoted gene expressions of BMP‐5 and BMP‐7 in ECs.…”