Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1.
Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1.
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Urocortin-1通过调节Piezo 1对急性腕关节损伤具有软骨保护作用。
DOI：
10.3390/ijms23095119
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发表时间：
2022-05-04
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
创伤后OA（PTOA）通常由损伤性高冲击负荷事件触发，导致软骨细胞快速过度死亡，残留细胞表型向更分解代谢状态转变。因此，鉴定一种可以保护软骨细胞免受撞击损伤后死亡的疾病修饰OA药物（DMOAD），从而防止软骨降解和进展为PTOA，将提供一种新的干预措施。我们以前已经表明，尿皮质素-1（UCN）是一种重要的内源性促生存因子，可保护软骨细胞免受OA相关促凋亡刺激。在这里，使用落塔PTOA诱导模型，我们证明了在软骨外植体暴露于过度的冲击负荷的程度UCN的软骨保护作用。使用通路特异性激动剂和拮抗剂，我们表明，UCN的行为，以阻止负载诱导的细胞内钙积累，通过封锁的非选择性阳离子通道Piezo 1，而不是TRPV 4。这种保护作用主要通过Ucn受体CRF-R1而不是CRF-R2介导。至关重要的是，我们证明了UCN的软骨保护作用是保持无论是施加前的影响或后的影响，突出了UCN作为一种新的DMOAD的潜力，用于预防有害的影响过载引起的PTOA。
Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn’s chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA.
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