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

Abstract

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.

Naringin promotes differentiation of bone marrow stem cells into osteoblasts by upregulating the expression levels of microRNA-20a and downregulating the expression levels of PPARγ

“…Osteoblasts determine not only the rate of bone formation, they also adjust the activity levels of osteoclasts, thereby determining the rate of bone resorption (22). Bone formation includes three stages: Osteoblast proliferation, osteoblast maturation, and mineralization of the extracellular matrix.…”

Hypoxic regulation of osteoclast differentiation and bone resorption activity

“…Taken at face value, it would seem that osteoclast activity is more sensitive to HIF inhibition and that bone formation is more sensitive to HIF activation, potentially due to HIF-dependent induction of OPG, an inhibitor of osteoclast activity. 95 , 101 Intriguingly, intervention in either direction apparently tips the homeostatic balance back in favor of maintaining or improving bone integrity.…”

Osteoblast Hypoxia-Inducible Factor-1α Pathway Activation Restrains Osteoclastogenesis via the Interleukin-33-MicroRNA-34a-Notch1 Pathway

“…Osteoblasts HIF-1α signaling pathway activation by Vhl or PHD silencing plays a critical role in bone homeostasis by regulating osteoclastogenesis through OPG ( 12 , 13 ). However, it is unclear whether osteoblast HIF-1α activation can mediate osteoclastogenesis through other “paracrine” approaches.…”

“…Our results reveal that HIF-1α in osteoblasts accelerates angiogenesis as well as osteogenesis via increasing vascular endothelial growth factor (VEGF) expression during bone development ( 10 , 11 ), and upregulated VEGF expression in Vhl -deficient osteoblasts facilitates bone marrow stromal cells (BMSCs) proliferation and osteogenic differentiation ( 11 ). In addition to coordinating osteoblastic–angiogenic coupling, both VHL/HIF and PHD/HIF signaling pathways in osteoblasts have been proved to facilitate bone homeostasis by regulating osteoclastogenesis through the direct regulation of OPG ( 12 , 13 ). Thus, besides increasing angiogenesis or osteoblastic activity, hypoxia/HIF-1α pathway activation pormotes bone development may also via disturbing osteoblast and osteoclast coupling and thereby dampens osteoclast activation.…”