Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway

International Journal of Molecular Sciences

Zhaojia Wu¹  Cuihong Fan¹  Jim Xiang¹  David M. L. Cooper²  Adam Magnus²  Kim Harrison²  B. Frank Eames²  Junqiong Huang³  Rajni Chibbar⁴  Gary Groot⁵  Harald Genth⁶  Xing Tan⁷  Yulin Deng⁷  Jun Zhang⁷ 

[1] Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK S7N 4H4, Canada;Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada;Department of Blood Transfusion, Affiliated Hospital of Zunyi Medical University, Zunyi 563006, China;Department of Pathology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada;Department of Surgery, Royal University Hospital, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada;Institute of Toxicology, Hannover Medical School, D-30625 Hannover, Germany;School of Life Sciences, Beijing Institute of Technology, Beijing 100811, China;

关键词: SMG;    FAK;    Wnt/β-catenin;    osteoblast;    ALP activity;    mineralization;   

DOI  :  10.3390/ijms23105593

来源: DOAJ

【 摘 要 】

Simulated microgravity (SMG) inhibits osteoblast differentiation (OBD) and induces bone loss via the inhibition of the Wnt/β-catenin pathway. However, the mechanism by which SMG alters the Wnt/β-catenin pathway is unknown. We previously demonstrated that SMG altered the focal adhesion kinase (FAK)-regulated mTORC1, AMPK and ERK1/2 pathways, leading to the inhibition of tumor cell proliferation/metastasis and promoting cell apoptosis. To examine whether FAK similarly mediates SMG-dependent changes to Wnt/β-catenin in osteoblasts, we characterized mouse MC3T3-E1 cells cultured under clinostat-modeled SMG (µg) conditions. Compared to cells cultured under ground (1 g) conditions, SMG reduces focal adhesions, alters cytoskeleton structures, and down-regulates FAK, Wnt/β-catenin and Wnt/β-catenin-regulated molecules. Consequently, protein-2 (BMP2), type-1 collagen (COL1), alkaline-phosphatase activity and matrix mineralization are all inhibited. In the mouse hindlimb unloading (HU) model, SMG-affected tibial trabecular bone loss is significantly reduced, according to histological and micro-computed tomography analyses. Interestingly, the FAK activator, cytotoxic necrotizing factor-1 (CNF1), significantly suppresses all of the SMG-induced alterations in MC3T3-E1 cells and the HU model. Therefore, our data demonstrate the critical role of FAK in the SMG-induced inhibition of OBD and bone loss via the Wnt/β-catenin pathway, offering FAK signaling as a new therapeutic target not only for astronauts at risk of OBD inhibition and bone loss, but also osteoporotic patients.

【 授权许可】

Unknown