Activation of HIFa pathway in mature osteoblasts disrupts the integrity of the osteocyte/canalicular network

• Published in: PloS one 2015-03, Vol.10 (3), p.e0121266-e0121266
• Main Authors: Zuo, Gui-lai, Zhang, Lian-fang, Qi, Jin, Kang, Hui, Jia, Peng, Chen, Hao, Shen, Xing, Guo, Lei, Zhou, Han-bing, Wang, Jin-shen, Zhou, Qi, Qian, Nian-dong, Deng, Lian-fu
• Format: Article
• Language: English
• Subjects: Activation; Animals; Apoptosis; Biocompatibility; Bone (cortical); Bone growth; Bone marrow; Cell Differentiation; Cell proliferation; Cell Shape - physiology; Cortical bone; Cytology; Deactivation; Differentiation (biology); Disease prevention; Genetic research; Hippel-Lindau gene; Hospitals; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Inactivation; Insulin-like growth factors; Laboratories; Medicine; Mice; Mice, Knockout; Microscopy; Morphology; Neoplasia; Osteoblasts; Osteoblasts - cytology; Osteoblasts - metabolism; Osteocytes; Osteocytes - cytology; Osteocytes - metabolism; Osteogenesis; Osteogenesis - physiology; Oxygen; Signal Transduction - physiology; Stromal cells; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; β-Catenin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0121266

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.