TRPC1 links calcium signaling to cellular senescence in the protection against post-traumatic osteoarthritis

Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we have demonstrated that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence associated cartilage breakdown during mechanical and inflammatory challenge. We revealed that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a non-redundant role in calcium signaling in chondrocytes. Trpc1-/- mice subjected to destabilization of the medial meniscus induced OA developed a more severe OA phenotype than wild type controls. During early OA development, Trpc1-/- mice displayed an increased chondrocyte survival rate, however remaining cells displayed features of senescence including p16INK4a expression and decreased Sox9. RNA sequencing identified differentially expressed genes related to cell number, apoptosis and extracellular matrix organization. Trpc1-/- chondrocytes exhibited accelerated dedifferentiation, while demonstrating an increased susceptibility to cellular senescence. Targeting the mechanism of TRPC1 activation may be a promising therapeutic strategy in osteoarthritis prevention. Overall design: RNA sequencing of murine knee joint articular cartilage collected 2 weeks post destabilisation of the medial meniscus (DMM) surgery, comparing wild type and Trpc1-/- male mice operated at 10 weeks of age

瞬时受体电位通道1（TRPC1）是一类广泛表达的机械敏感性离子通道，定位于内质网膜，在钙依赖性信号通路激活过程中，对补充耗尽的内钙储库至关重要。本研究证实，TRPC1的活性在软骨稳态中发挥保护作用，可预防机械与炎症刺激下与细胞衰老相关的软骨退变。研究发现，TRPC1的缺失与骨关节炎（OA）的早期阶段密切相关，并在软骨细胞的钙信号传导中发挥非冗余作用。对Trpc1基因敲除（Trpc1-/-）小鼠实施内侧半月板失稳术诱导骨关节炎后，其骨关节炎表型较野生型对照小鼠更为严重。在骨关节炎早期进程中，Trpc1-/-小鼠的软骨细胞存活率有所升高，但剩余细胞呈现出衰老相关特征，包括p16INK4a表达上调以及Sox9表达降低。RNA测序结果显示，差异表达基因与细胞数量、细胞凋亡及细胞外基质组织相关。Trpc1-/-软骨细胞表现出加速的去分化现象，同时对细胞衰老的易感性增强。靶向调控TRPC1的激活机制或可成为预防骨关节炎的潜在治疗策略。整体实验设计：对10周龄雄性野生型与Trpc1-/-小鼠实施内侧半月板失稳（DMM）术后2周，采集其膝关节关节软骨进行RNA测序，并对两组样本进行比较。