Mechanical loading rescues mechanoresponsiveness in a human osteoarthritis explant model despite Wnt activation

Objectives Optimizing rehabilitation strategies for osteoarthritis necessitates a comprehensive understanding of chondrocytes’ mechanoresponse in both health and disease, especially in the context of the interplay between loading and key pathways involved in osteoarthritis development, like canonical Wnt signaling. This study aims to elucidate the role of Wnt signaling in the mechanoresponsiveness of healthy and osteoarthritic human cartilage. Methods We used an ex-vivo model involving short-term physiological mechanical loading of human cartilage explants. First, the loading protocol for subsequent experiments was determined. Next, loading was applied to non-OA explants with or without Wnt activation with CHIR99021. Molecular read-outs of anabolic, pericellular matrix and matrix remodeling markers were used to assess the effect of Wnt on cartilage mechanoresponse. Finally, the same set-up was used to study the effect of loading in cartilage from patients with established OA. Results Our results confirm that physiological loading maintains expression of anabolic genes in non-OA cartilage, but indicate a deleterious effect of Wnt activation in the chondrogenic mechanoresponsiveness. This suggests that loading-induced regulation of cartilage markers occurs downstream of canonical Wnt signaling. Interestingly, our study highlighted contrasting mechanoresponsiveness in the model of Wnt activation and the established OA samples, with established OA cartilage maintaining its mechanoresponsiveness, and mechanical loading rescuing the chondrogenic phenotype. Conclusion This study provides insights into the mechanoresponsiveness of human cartilage in both non-OA and OA conditions. These findings hold the potential to contribute to the development of strategies that optimize the effect of dynamic compression by correcting OA pathological cell signaling.