Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation

被引:26
|
作者
Thompson, Clare L. [1 ]
McFie, Megan [1 ]
Chapple, J. Paul [2 ]
Beales, Philip [3 ]
Knight, Martin M. [1 ]
机构
[1] Queen Mary Univ London, Sch Engn & Mat Sci, Ctr Predict Vitro Models, London E1 4NS, England
[2] Queen Mary Univ London, Sch Med & Dent, William Harvey Res Inst, Ctr Endocrinol, London EC1M 6BQ, England
[3] UCL Great Ormond St Inst Child Hlth, Genet & Genom Med, London WC1N 1EH, England
基金
英国医学研究理事会;
关键词
Polycystin; Polycystin-1; Polycystin-2; cilia; strain; cartilage; chondrocyte; mechanotransduction; C-TERMINAL FRAGMENT; GENE-EXPRESSION; INTRAFLAGELLAR TRANSPORT; ALPHA-5-BETA-1; INTEGRIN; ARTICULAR CHONDROCYTES; EXTRACELLULAR ATP; STEM-CELLS; RELEASE; STRAIN; DISEASE;
D O I
10.3390/ijms22094313
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Primary cilia and associated intraflagellar transport are essential for skeletal development, joint homeostasis, and the response to mechanical stimuli, although the mechanisms remain unclear. Polycystin-2 (PC2) is a member of the transient receptor potential polycystic (TRPP) family of cation channels, and together with Polycystin-1 (PC1), it has been implicated in cilia-mediated mechanotransduction in epithelial cells. The current study investigates the effect of mechanical stimulation on the localization of ciliary polycystins in chondrocytes and tests the hypothesis that they are required in chondrocyte mechanosignaling. Isolated chondrocytes were subjected to mechanical stimulation in the form of uniaxial cyclic tensile strain (CTS) in order to examine the effects on PC2 ciliary localization and matrix gene expression. In the absence of strain, PC2 localizes to the chondrocyte ciliary membrane and neither PC1 nor PC2 are required for ciliogenesis. Cartilage matrix gene expression (Acan, Col2a) is increased in response to 10% CTS. This response is inhibited by siRNA-mediated loss of PC1 or PC2 expression. PC2 ciliary localization requires PC1 and is increased in response to CTS. Increased PC2 cilia trafficking is dependent on the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4) activation. Together, these findings demonstrate for the first time that polycystins are required for chondrocyte mechanotransduction and highlight the mechanosensitive cilia trafficking of PC2 as an important component of cilia-mediated mechanotransduction.
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页数:16
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