Curcumin mediated suppression of nuclear factor-KB promotes chondrogenic differentiation of mesenchymal stem cells in a high-density co-culture microenvironment

Introduction: Osteoarthritis (OA) and rheumatoid arthritis (RA) are characterised by joint inflammation and cartilage degradation. Although mesenchymal stem cell (MSC)-like progenitors are resident in the superficial zone of articular cartilage, damaged tissue does not possess the capacity for regeneration. The high levels of pro-inflammatory cytokines present in OA/RA joints may impede the chondrogenic differentiation of these progenitors. Interleukin (IL)-1 beta activates the transcription factor nuclear factor-KB (NF-KB), which in turn activates proteins involved in matrix degradation, inflammation and apoptosis. Curcumin is a phytochemical capable of inhibiting IL-1 beta-induced activation of NF-KB and expression of apoptotic and pro-inflammatory genes in chondrocytes. Therefore, the aim of the present study was to evaluate the influence of curcumin on IL-1 beta-induced NF-KB signalling pathway in MSCs during chondrogenic differentiation. Methods: MSCs were either cultured in a ratio of 1:1 with primary chondrocytes in high-density culture or cultured alone in monolayer with/without curcumin and/or IL-1 beta. Results: We demonstrate that although curcumin alone does not have chondrogenic effects on MSCs, it inhibits IL-1 beta-induced activation of NF-KB, activation of caspase-3 and cyclooxygenase-2 in MSCs time and concentration dependently, as it does in chondrocytes. In IL-1 beta stimulated co-cultures, four-hour pre-treatment with curcumin significantly enhanced the production of collagen type II, cartilage specific proteoglycans (CSPGs), beta 1-integrin, as well as activating MAPKinase signaling and suppressing caspase-3 and cyclooxygenase-2. Conclusions: Curcumin treatment may help establish a microenvironment in which the effects of pro-inflammatory cytokines are antagonized, thus facilitating chondrogenesis of MSC-like progenitor cells in vivo. This strategy may support the regeneration of articular cartilage.