Curcumin synergizes with resveratrol to stimulate the MAPK signaling pathway in human articular chondrocytes in vitro

The mitogen-activated protein kinase (MAPK) pathway is stimulated in differentiated chondrocytes and is an important signaling cascade for chondrocyte differentiation and survival. Pro-inflammatory cytokines such as interleukin 1 beta (IL-1 beta) play important roles in the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA). In this study, we investigated whether curcumin and resveratrol can synergistically inhibit the catabolic effects of IL-1 beta, specifically the inhibition of the MAPK and subsequent apoptosis in human articular chondrocytes. Chondrocytes were either left untreated or treated with 10 ng/ml IL-1 beta or 1 mu M U0126, a specific inhibitor of MAPK pathway alone for the indicated time periods or pre-treated with 10 mu M curcumin, 10 mu M resveratrol or 10 mu M resveratrol and 10 mu M curcumin for 4 h followed by co-treatment with 10 ng/ml IL-1 beta or 1 mu M U0126 and 10 mu M resveratrol, 10 mu M curcumin or 10 mu M resveratrol and 10 mu M curcumin for the indicated time periods. Cultures were evaluated by immunoblotting and transmission electron microscopy. Incubation of chondrocytes with IL-1 beta resulted in induction of apoptosis, downregulation of beta 1-integrins and the extracellular signal-regulated kinase 1/2 (Erk1/2). Interestingly, U0126 induced apoptosis and blocked the above-mentioned proteins in a similar way to IL-1 beta. Furthermore, curcumin and resveratrol inhibited IL-1 beta- or U0126-induced apoptosis and downregulation of beta 1-integrins and Erk1/2 in human articular chondrocytes. These results suggest that combining these two natural compounds activates MEK/Erk signaling, a pathway that is involved in the maintenance of chondrocyte differentiation and survival.