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

Gui-lai Zuo; Lian-fang Zhang; Jin Qi; Hui Kang; Peng Jia; Hao Chen; Xing Shen; Lei Guo; Han-bing Zhou; Jin-shen Wang; Qi Zhou; Nian-dong Qian; Lian-fu Deng

doi:10.1371/journal.pone.0121266

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

PLoS One. 2015 Mar 25;10(3):e0121266. doi: 10.1371/journal.pone.0121266. eCollection 2015.

Authors

Gui-lai Zuo¹, Lian-fang Zhang², Jin Qi³, Hui Kang³, Peng Jia³, Hao Chen³, Xing Shen³, Lei Guo³, Han-bing Zhou³, Jin-shen Wang³, Qi Zhou³, Nian-dong Qian³, Lian-fu Deng³

Affiliations

¹ Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China; Department of Orthopaedics, Qian Fo Shan Hospital, Shang Dong University, Ji Nan, China.
² Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
³ Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cell Shape / physiology
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Mice
Mice, Knockout
Osteoblasts / cytology
Osteoblasts / metabolism*
Osteocytes / cytology
Osteocytes / metabolism*
Osteogenesis / physiology*
Signal Transduction / physiology*
Von Hippel-Lindau Tumor Suppressor Protein / genetics
Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
Von Hippel-Lindau Tumor Suppressor Protein

Grants and funding

Deng Lian Fu received funds from Natural Science Foundation of China (No. 81371958, 81061160510), the Basic Key Project of Science and Technology Commission of Shanghai Municipality (12JC1408200), and the Scientific and Technological Support Program in Biological Medicine of Science and Technology Commission of Shanghai Municipality (13431900702), http://www.nsfc.gov.cn/, http://www.stcsm.gov.cn/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.