ADAMTS5在骨关节炎中的生物学功能、调节网络和潜在的靶向治疗,Frontiers in Molecular Biosciences

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ADAMTS5在骨关节炎中的生物学功能、调节网络和潜在的靶向治疗
Frontiers in Molecular Biosciences ( IF 3.9 ) Pub Date : 2021-07-05 , DOI: 10.3389/fmolb.2021.703110
Lejian Jiang _{1,

2} , Jiachen Lin _{3,

4,

5} , Sen Zhao _{3,

4,

5} , Jiaqian Wu ₁ , Yongming Jin ₁ , Li Yu ₆ , Nan Wu _{3,

4,

5} , Zhihong Wu _{4,

5,

7} , Yue Wang _{1,

2} , Mao Lin _{1,

2,

4,

7}

Affiliation

ADAMTS5 参与 OA 的发病机制。作为主要的蛋白聚糖酶降解关节软骨基质，ADAMTS5 已被视为 OA 治疗的潜在靶点。我们在这里提供了对 ADAMTS5 调控的最新见解和新发现的 OA 治疗策略。讨论了关节炎症和机械转导以及软骨细胞肥大的病理生理学和分子机制，并分别回顾了 ADAMTS5 在每个生物过程中的作用。ADAMTS5 的过度激活涉及衰老、遗传、炎症和机械应激，从而导致 OA 的发病机制。观察到多种分子信号通路调节 ADAMTS5 的表达，即 Runx2、YAP/TAZ、Notch、Wnt、NF-κB 和其他炎症信号通路。然而，分子调控网络尚未阐明，ADAMTS5 的时空表达模式仍未阐明。基于对 ADAMTS5 在 OA 发病机制中的基本认识，开发了针对 ADAMTS5 的单克隆抗体和小分子抑制剂，并在体外和体内均证明是有益的。最近的新型 RNA 疗法在 OA 动物模型中显示出对 ADAMTS5 具有高度特异性的显着抑制作用。总之，ADAMTS5 抑制及其基于信号通路的 RNA 疗法在未来的 OA 治疗策略中显示出巨大的潜力。开发了针对 ADAMTS5 的单克隆抗体和小分子抑制剂，并在体外和体内均证明是有益的。最近的新型 RNA 疗法在 OA 动物模型中表现出对 ADAMTS5 具有高度特异性的显着抑制作用。总之，ADAMTS5 抑制及其基于信号通路的 RNA 疗法在未来的 OA 治疗策略中显示出巨大的潜力。开发了针对 ADAMTS5 的单克隆抗体和小分子抑制剂，并在体外和体内均证明是有益的。最近的新型 RNA 疗法在 OA 动物模型中表现出对 ADAMTS5 具有高度特异性的显着抑制作用。总之，ADAMTS5 抑制及其基于信号通路的 RNA 疗法在未来的 OA 治疗策略中显示出巨大的潜力。

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ADAMTS5 in osteoarthritis: biological functions, regulatory network, and potential targeting therapies

ADAMTS5 involves in the pathogenesis of OA. As the major aggrecanase degrading articular cartilage matrix, ADAMTS5 has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, heredity, inflammation and mechanical stress are involved in the over-activation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, YAP/TAZ, Notch, Wnt, NF-κB and the other inflammatory signaling pathways. However, the molecular regulatory network has not yet been elucidated, and the spatio-temporal expression pattern of ADAMTS5 remains unclarified. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved beneficial both in vitro and in vivo. Recent novel RNA therapies demonstrated significant suppressive effect on ADAMTS5 with high specificity in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway-based RNA therapies showed great potential in future therapeutic strategies for OA.

更新日期：2021-07-05

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