Activation of the bile acid receptor GPBAR1 (TGR5) ameliorates interleukin-1β (IL-1β)- induced chondrocytes senescence.

Osteoarthritis is the most common chronic condition of the joint disease. Chondrocyte is the sole cell type in joint tissues. Senescence of chondrocytes is known to contribute to the causation of osteoarthritis. Local inflammatory cytokines- caused chondrocytes senescence is proposed to be one of the molecular mechanisms of osteoarthritis. In this study, we show that the bile acid receptor GPBAR1 (TGR5), a G protein couples bile acid receptor, plays important roles in protecting chondrocytes from interleukin 1β (IL-1β)- caused senescence. TGR5 is fairly expressed in cultured chondrocytes. Its expression is reduced in isolated chondrocytes from osteoarthritis patients, and IL-1β treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic agonist, INT-777, dramatically reduces senescence associated β galactosidase activity by IL-1β. Mechanistically, the action of INT-777 ameliorates IL-1β- induced chondrocytes entry of G0/G1 arrest phase and exit of S and G2/M phases. INT-777 inhibits IL-1β- induced expression of p21, PAI-1, and K382 acetylation of p53 as well as reduction of Sirt1. The knockdown of TRG5 abolished the protective role of INT-777 on these molecules. Collectively, our data indicates that activation of TGR5 is necessary for protection of IL-1β- induced chondrocytes senescence.