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Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis.
Biomaterials ( IF 12.8 ) Pub Date : 2019-12-26 , DOI: 10.1016/j.biomaterials.2019.119724
Xianzhu Zhang 1 , Dandan Cai 2 , Feifei Zhou 2 , Jie Yu 2 , Xinyu Wu 2 , Dongsheng Yu 3 , Yiwei Zou 2 , Yi Hong 1 , Chunhui Yuan 2 , Yishan Chen 2 , Zongyou Pan 3 , Varitsara Bunpetch 2 , Heng Sun 2 , Chengrui An 2 , Toh Yi-Chin 4 , Hongwei Ouyang 5 , Shufang Zhang 6
Affiliation  

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.

中文翻译:

用Verteporfin封装的壳聚糖微球靶向下游亚细胞YAP活性作为基质刚度的函数,可减轻骨关节炎。

软骨细胞外基质(ECM)硬度的变化与骨关节炎(OA)的病理进展有关。但是,软骨ECM硬度的下游反应仍不清楚。YAP(是相关蛋白)已被广泛研究为机械转导剂,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中的软骨变性。在这里,我们表明人软骨基质在OA病理过程中变硬,而软骨细胞YAP活性与ECM僵硬相关。然后,我们使用基于PDMS的底物模拟了人类软骨的生理和病理学刚度,发现YAP在接种于硬底物的软骨细胞中被激活,逐渐失去其表型。另外,观察到YAP在小鼠OA发育中也被显着激活,并且在小鼠中YAP的条件性敲除(cKO)在OA模型中保留了胶原II的表达并保护了软骨免于变性。此外,关节腔内注射YAP选择性抑制剂Verteporfin可显着维持小鼠OA模型的软骨稳态。这项研究表明,以机械换能器为靶标的药物的应用可能是OA软骨修复的潜在治疗方法。在小鼠OA模型中显着维持软骨稳态。这项研究表明,以机械换能器为靶标的药物的应用可能是OA软骨修复的潜在治疗方法。在小鼠OA模型中显着维持软骨稳态。这项研究表明,以机械换能器为靶标的药物的应用可能是OA软骨修复的潜在治疗方法。
更新日期:2019-12-27
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