Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis
Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis
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使用维替泊芬封装的壳聚糖微球靶向下游亚细胞 YAP 活性作为基质硬度的函数，从而减轻骨关节炎
DOI：
10.1016/j.biomaterials.2019.119724
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发表时间：
2020
期刊：
影响因子：
14
通讯作者：
Zhang Shufang
中科院分区：
文献类型：
--
作者：
Zhang Xianzhu;Cai D;an;Zhou Feifei;Yu Jie;Wu Xinyu;Yu Dongsheng;Zou Yiwei;Hong Yi;Yuan Chunhui;Chen Yishan;Pan Zongyou;Bunpetch Varitsara;Sun Heng;An Chengrui;Yi-Ching Toh;Ouyang Hongwei;Zhang Shufang
软骨细胞细胞外基质（ECM）硬度的变化参与骨关节炎（OA）的病理进展。然而，软骨 ECM 硬度的下游反应仍不清楚。 YAP（Yes 相关蛋白）作为一种力传感器已被广泛研究，因此我们假设通过靶向 ECM 硬度的下游分子活性可以维持软骨细胞表型并防止 OA 中的软骨退化。在这里，我们发现人类软骨基质在 OA 病理进展过程中变硬，并且软骨细胞 YAP 活性与 ECM 硬度相关。然后，我们使用基于PDMS的基质模拟了人类软骨的生理和病理硬度，发现YAP在接种于坚硬基质上的软骨细胞中被激活，逐渐失去其表型。此外，观察到 YAP 在小鼠 OA 发展过程中也被显着激活，小鼠中 YAP 的条件敲除 (cKO) 保留了 II 型胶原蛋白的表达，并保护 OA 模型中的软骨免于退化。此外，关节内注射 YAP 选择性抑制剂维替泊芬可显着维持小鼠 OA 模型中的软骨稳态。这项研究表明，机械传感器靶向药物的应用可能成为骨关节炎软骨修复的潜在治疗方法。
Changes in the stiffness of chondrocyte extracellular matrix (ECM) are involved in the pathological progression of osteoarthritis (OA). However, the downstream responses of cartilage ECM stiffness are still unclear. YAP (Yes-associated protein) has been extensively studied as a mechanotransducer, we thus hypothesized that by targeting the downstream molecule activity of ECM stiffness could maintain chondrocyte phenotype and prevent cartilage degeneration in OA. Here, we showed that human cartilage matrix stiffened during pathological progression of OA, and the chondrocyte YAP activity was associated with ECM stiffness. We then mimicked the physiological and pathological stiffness of human cartilage by using PDMS-based substrates, and found that YAP was activated in chondrocytes seeded on stiff substrate, gradually losing their phenotype. In addition, it was observed that YAP was also significantly activated in mice OA development, and conditional knockout (cKO) of YAP in mice preserved collagen II expression and protected cartilage from degeneration in the OA model. Furthermore, intra-articular injection of YAP-selective inhibitor, Verteporfin, significantly maintained cartilage homeostasis in mice OA model. This study indicates that the application of mechanotransducer-targeted drugs could be a potential therapeutic approach for cartilage repair in OA.