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

• Published in: International journal of molecular sciences 2022-05, Vol.23 (10), p.5593
• Main Authors: Fan, Cuihong, Wu, Zhaojia, Cooper, David M L, Magnus, Adam, Harrison, Kim, Eames, B Frank, Chibbar, Rajni, Groot, Gary, Huang, Junqiong, Genth, Harald, Zhang, Jun, Tan, Xing, Deng, Yulin, Xiang, Jim
• Format: Article
• Language: English
• Subjects: Adhesion; ALP activity; Apoptosis; Astronauts; Biomedical materials; Bone density; Bone loss; Bone morphogenetic protein 2; Cancellous bone; Cell division; Cell proliferation; Collagen; Computed tomography; Cytoskeleton; Cytotoxic necrotizing factor 1; Cytotoxicity; Differentiation; Extracellular signal-regulated kinase; FAK; Focal adhesion kinase; Gene expression; Kinases; Localization; Metastases; Microscopy; Mineralization; osteoblast; Osteoblastogenesis; Osteoblasts; Osteoporosis; Physiology; Proteins; SMG; Therapeutic targets; Transcription factors; Tumors; Wnt protein; Wnt/β-catenin; β-Catenin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23105593

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.