Periodic Mechanical Stress Stimulates the FAK Mitogenic Signal in Rat Chondrocytes Through ERK1/2 Activity

Cellular Physiology and Biochemistry

关键词: Matrix synthesis;    FAK;    Src;    Integrin β1;    Periodic mechanical stress;    Chondrocyte proliferation;   

DOI  :  10.1159/000354495

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims The biological effects of periodic mechanical stress on chondrocytes have been studied extensively over the past few years. However, the mechanisms underlying chondrocyte mechanosensing and signaling in response to periodic mechanical stress remain to be determined. In the current study, we examined the effects of focal adhesion kinase (FAK) signaling on periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis. Methods and Results Periodic mechanical stress significantly induced sustained phosphorylation of FAK at Tyr³⁹⁷ and Tyr^576/577. Reduction of FAK with targeted shRNA via transfection of NH₂-terminal tyrosine phosphorylation-deficient FAK mutant Y397F or Y576F-Y577F abolished periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis, accompanied by attenuated ERK1/2 phosphorylation. However, activation of Src, PLCγ1 and Rac1 was not prevented upon FAK suppression. Furthermore, pretreatment with the Src-selective inhibitor, PP2, and shRNA targeted to Src or suppression of Rac1 with its selective inhibitor, NSC23766, blocked FAK phosphorylation at Tyr,^576/577 but not Tyr,³⁹⁷ under periodic mechanical stress. Interestingly, FAK phosphorylation neither at Tyr³⁹⁷ nor at Tyr^576/577 was affected by PLCγ1 depletion when periodic mechanical stress was applied. In addition, Tyr³⁹⁷ and Tyr^576/577 phosphorylation levels were reduced upon pretreatment with a blocking antibody against integrin β1 under conditions of periodic mechanical stress. Conclusion Our findings collectively suggest that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis through at least two pathways, integrin β1-Src-Rac1-FAK(Tyr^576/577)-ERK1/2 and integrin β1-FAK (Tyr³⁹⁷)-ERK1/2.

【 授权许可】

CC BY-NC-ND