Berberine attenuates CCN2-induced IL-1β expression and prevents cartilage degradation in a rat model of osteoarthritis

Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator that is abundantly expressed in osteoarthritis (OA). Interleukin-1 beta (IL-1 beta) plays a pivotal role in OA pathogenesis. Berberine exhibits an anti-inflammatory effect, but the mechanisms by which it modulates CCN2-induced IL-1 beta expression in OA synovial fibroblasts (OASFs) remain unknown. We showed that CCN2-induced IL-1 beta expression is mediated by the activation of alpha(v)beta 3/alpha(v)beta 5 integrin-dependent reactive oxygen species (ROS) generation, and subsequent activation of apoptosis signal-regulating kinase 1 (ASK1), p38/JNK, and nuclear factor-kappa B (NF-kappa B) signaling pathways. This IL-1 beta expression in OASFs is attenuated by N-acetylcysteine (NAC), inhibitors of ASK1, p38, or JNK, or treatment with berberine. Furthermore, berberine also reverses cartilage damage in an experimental model of collagenase-induced OA (CIOA). We observed that CCN2 increased IL-1 beta expression via alpha(v)beta 3/alpha(v)beta 5 integrins, ROS, and ASK1, p38/JNK, and NF-kappa B signaling pathways. Berberine was found to inhibit these signaling components in OASFs in vitro and prevent cartilage degradation in vivo. We suggest a novel therapeutic strategy of using berberine for managing OA. (C) 2015 Elsevier Inc. All rights reserved.