Mechanosensitive signalling complexes as early targets of post-traumatic osteoarthritis (OA)

T. Pap & J. Bertrand, IEMM, Uniklinikum Münster

Abstract: Articular cartilage has a special importance for reducing mechanical stress during movement, and multiple lines of evidence suggest that overload translates into a specific chondrocyte response leading to osteoarthritis. The question, however, of how chondrocytes sense mechanical stress and how this results in the loss of their phenotypic stability remains largely unclear. We hypothesise that mechano-sensitive signaling complexes as composed of adhesion molecules and membrane anchored calcium channels are important mediators and, thus, therapeutic targets of osteoarthritis. Recent work of our group has identified syndecans (sdc’s), particularly sdc-4, as surface molecule on chondrocytes, the loss or inhibition of which leads to resistance against osteoarthritis. Of note, sdc-4 regulates the expression of transient receptor potential calcium channels (TRPC) that can sense mechanical stress and regulate the response to factors involved in maintaining the phenotypic stability of chondrocytes. According to our hypothesis sdc’s and TRPCs are key parts of mechanosensitive signaling complexes in chondrocytes, and based on our above data we plan to use a combined approach of well established molecular and cell biology techniques as well as preclinical in vivo models of osteoarthritis  available both in the OVERLOAD and the PreVOP consortium to study the function of TRPCs (TRPC6, TRPC1) in chondrocytes and the interplay between sdc’s (sdc-1, sdc-4) and these TRPCs. A focus will be on the characterization of signaling pathways that trigger the phenotypic switch in chondrocytes as induced by mechanical and non-mechanical stress. Using TRPC activators and inhibitors together with genetically modified mice we will dissect the role of TRPCs from sdc- mediated effects and study the underlying pathways. Overall this study will aim at elucidating the therapeutic potential of sdc- and TRPC- blockade to prevent and treat mechanically- induced changes in chondrocytes and provide the data to the members of both the OVERLOAD and the PrevOP consortium.

 

 

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