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

The hypoxia-inducible factors (HIFs), HIF-1 alpha and HIF-2 alpha, 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 HIF alpha signaling. Here we show that inactivation of Vhl in mature osteoblasts/osteocytes induces their apoptosis and disrupts the cell/canalicular network. VHL-deficient (Delta VHL) 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 beta-catenin in the BMSC. Our data suggest that the VHL/HIF alpha 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 beta-catenin in the osteoblasts/osteoprogenitors of the bone marrow.