Final Report Summary - EUCUREOA (SirT1 Regulation of Aggrecan Expression in Human Chondrocytes)
Numerous reports show that enhanced exposure to inflammatory cytokines is an integral part of OA progression. To this end, my group has additionally investigated the effect inflammatory mediators on Sirt1, and the attributes of such alterations in cartilage biology and homeostasis. Our observations established that the lysosomal cathepsin B cleaves Sirt1 in human chondrocytes treated with TNFalpha and/or IL1beta. We additionally show that this cleaved fragment (75kDa Sirt1; 75Sirt1) could prolong chondrocyte viability under pro-inflammtory conditions. These data were further validated in-vivo using a comparison between Sirt1 w.t. and haploinsufficient mice at young (1 month) and in older ages (9 months).
Expectedly, research obtained regarding Sirt1 in cartilage biology, will impact the generation of novel disease-modifying drugs to modulate Sirt1 activity and prevent age-related cartilage degeneration, as seen in OA.