Resveratrol counteracts IL‐1β‐mediated impairment of extracellular matrix deposition in 3D articular chondrocyte constructs

When aiming at cell-based therapies in osteoarthritis (OA), pro-inflammatory conditions mediated by cytokines such as IL-1beta need to be considered. In recent studies, the phytoalexin resveratrol (RSV) has exhibited potent anti-inflammatory properties. However, long-term effects on 3D cartilaginous constructs under inflammatory conditions with regard to tissue quality, especially extracellular matrix (ECM) composition, have remained unexplored. Therefore, we employed long-term model cultures for cell-based therapies in an in vitro OA environment and evaluated effects of RSV. Pellet constructs made from expanded porcine articular chondrocytes were cultured with either IL-1beta (1-10 ng/ml) or RSV (50 muM) alone, or a co-treatment with both agents. Treatments were applied for 14 days, either directly after pellet formation or after a preculture period of 7 days. Culture with IL-1beta (10 ng/ml) decreased pellet size and DNA amount, and severely compromised glycosaminoglycan (GAG) and collagen content. Co-treatment with RSV distinctly counteracted the pro-inflammatory catabolism and led to partial rescue of the ECM composition in both culture systems, with especially strong effects on GAG. Marked MMP13 expression was detected in IL-1beta-treated pellets, but none upon RSV co-treatment. Expression of collagen type I was increased upon IL-1beta treatment and still observed when adding RSV, while collagen type X, indicating hypertrophy, was detected exclusively in pellets treated with RSV alone. In conclusion, RSV can counteract IL-1beta-mediated degradation and distinctly improve cartilaginous ECM deposition in 3D long-term inflammatory cultures. Nevertheless, potential hypertrophic effects should be taken into account when considering RSV as co-treatment for articular cartilage repair techniques.