Activation of HIFa Pathway in Mature Osteoblasts Disrupts the Integrity of the Osteocyte/Canalicular Network

Abstract

The hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, are the central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Previous studies indicated that disruption of the von Hippel-Lindau gene (Vhl) coincides with the activation of HIFα signaling. Here we show that inactivation of Vhl in mature osteoblasts/osteocytes induces their apoptosis and disrupts the cell/canalicular network. VHL-deficient (ΔVHL) mice exhibited a significantly increased cortical bone area resulting from enhanced proliferation and osteogenic differentiation of the bone marrow stromal cells (BMSCs) by inducing the expression of β-catenin in the BMSC. Our data suggest that the VHL/HIFα pathway in mature osteoblasts/osteocytes plays a critical role in the bone cell/canalicular network and that the changes of osteocyte morphology/function and cell/canalicular network may unleash the bone formation, The underlying mechanism of which was the accumulation of β-catenin in the osteoblasts/osteoprogenitors of the bone marrow.

Hormonal Regulation of Osteocyte Perilacunar and Canalicular Remodeling in the Hyp Mouse Model of X-Linked Hypophosphatemia

“…(38) Mice lacking metalloproteinase 2 (MMP2) or the von Hippel-Lindau gene (Vhl) also exhibit a decrease in number of canaliculi and canalicular connectivity associated with an increase in osteocyte apoptosis. (39,40) These mouse models support the important role of the osteocyte canalicular network on osteocyte viability.…”

Tao-Hong-Si-Wu Decoction ameliorates steroid-induced avascular necrosis of the femoral head by regulating the HIF-1α pathway and cell apoptosis

“…Bcl-2, Bcl-xl and Bid) as well (40,41). Since the HIF-1α signaling pathway has been found to be involved in regulation of the morphology/function of bone cells and osteoblasts (42), HIF-1α presumably plays a major role in the progression of SANFH.…”

Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects

“…The frequency of HIF-1-positive osteocytes increases in mice under disuse conditions [7]; in vitro, exposing osteocyte-like cells to hypoxia augments secretion of chemotactic factors [8] and GDF15 to promote osteoclastogenesis [9], and influences the osteoblast-to-osteocyte transition [10]. Other osteocytic functions attributed to HIF- function include directing appropriate bone formation in response to mechanical loading [11], sensing microdamage [12], and development of the lacunocanalicular network in which osteocytes reside [13].…”