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 (OA) development, like canonical Wnt signaling. This study aims to elucidate the role of Wnt signaling in the mechanoresponsiveness of healthy and osteoarthritic human cartilage. 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. Our results confirm that physiological loading maintains expression of anabolic genes in non-OA cartilage, and indicate a deleterious effect of Wnt activation in the chondrocyte mechanoresponsiveness. This suggests that loading-induced regulation of chondrocyte 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. 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.

中文翻译：

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尽管 Wnt 激活，机械负载仍可挽救人骨关节炎外植体模型的机械反应性

优化骨关节炎的康复策略需要全面了解软骨细胞在健康和疾病中的机械反应，特别是在负荷和骨关节炎 (OA) 发展中涉及的关键通路（如典型的 Wnt 信号传导）之间相互作用的背景下。本研究旨在阐明 Wnt 信号传导在健康和骨关节炎人类软骨的机械反应中的作用。我们使用了涉及人类软骨外植体短期生理机械负荷的离体模型。首先，确定后续实验的加载方案。接下来，用 CHIR99021 将负载应用于有或没有 Wnt 激活的非 OA 外植体。使用合成代谢、细胞周基质和基质重塑标记物的分子读数来评估 Wnt 对软骨机械反应的影响。最后，使用相同的装置来研究骨关节炎患者软骨负载的影响。我们的结果证实，生理负荷维持非 OA 软骨中合成代谢基因的表达，并表明 Wnt 激活对软骨细胞机械反应性的有害影响。这表明负荷诱导的软骨细胞标记物调节发生在经典 Wnt 信号传导的下游。有趣的是，我们的研究强调了 Wnt 激活模型和已建立的 OA 样本中对比的机械反应性，已建立的 OA 软骨保持其机械反应性，机械负荷挽救软骨形成表型。这项研究深入了解了人类软骨在非 OA 和 OA 条件下的机械响应性。这些发现有可能有助于制定通过纠正 OA 病理细胞信号传导来优化动态压缩效果的策略。