HIF-1α disturbs osteoblasts and osteoclasts coupling in bone remodeling by up-regulating OPG expression.

Hypoxia-inducible factor 1α (HIF-1α) is one of the master regulators of hypoxia reactions, playing an important role in bone modeling, remodeling, and homeostasis. And overexpression of HIF-1α in mature osteoblasts through conditional deletion of the von Hippel-Lindau (VHL) gene profoundly increases angiogenesis and osteogenesis. Studies showed that mice with osteoblasts lacking Vhl had a high level of Hif-1α and increased bone mass and density. On the contrary, Hif-1α conditional knockout mice had decreased bone mass and density. Our in vitro study showed that osteoprotegerin (OPG), an essential regulator of osteoclastic activity, can be upregulated by HIF-1α and in turn downregulate the resorption activity of osteoclasts. We showed that HIF-1α may directly bind to the upstream site of OPG and enhance its expression. Our study suggested that a novel mechanism, which works via OPG signaling, may mediate the function of HIF-1α in bone remodeling.