WNT Signalling in Osteoarthritis and Its Pharmacological Targeting.
WNT Signalling in Osteoarthritis and Its Pharmacological Targeting.
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DOI：
10.1007/164_2021_525
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发表时间：
2021-01-01
影响因子：
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通讯作者：
Nalesso, Giovanna
中科院分区：
文献类型：
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作者：
De Palma, Anna;Nalesso, Giovanna
骨关节炎（OA）是一种高度致残的肌肉骨骼疾病，影响全球数百万人。OA的特征在于关节组织和结构的进行性破坏和不可逆的形态学变化。在分子水平上，几种途径的失调有助于破坏关节中的组织稳态。WNT/β-连环蛋白信号通路的过度激活与OA的退行性过程相关。然而，在信号转导的调制和仍然不充分的知识的特定分子驱动器的致病机制的多层复杂性，使得难以药理学靶向该途径的治疗目的。本文综述了WNT/β-catenin信号在OA中的作用，特别关注其在关节软骨中的作用。其靶向显示出治疗潜力的通路组分将被突出和描述。一个特定的部分将致力于Lorecivint，第一个β-连环蛋白依赖性途径的抑制剂，目前在III期临床试验作为OA修饰剂。
Osteoarthritis (OA) is a highly disabling musculoskeletal condition affecting millions of people worldwide. OA is characterised by progressive destruction and irreversible morphological changes of joint tissues and architecture. At molecular level, de-regulation of several pathways contributes to the disruption of tissue homeostasis in the joint. Overactivation of the WNT/beta-catenin signalling pathway has been associated with degenerative processes in OA. However, the multiple layers of complexity in the modulation of the signalling and the still insufficient knowledge of the specific molecular drivers of pathogenetic mechanisms have made difficult the pharmacological targeting of this pathway for therapeutic purposes. This review aims to provide an overview of the WNT/beta-catenin signalling in OA with a particular focus on its role in the articular cartilage. Pathway components whose targeting showed therapeutic potential will be highlighted and described. A specific section will be dedicated to Lorecivivint, the first inhibitor of the beta-catenin-dependent pathway currently in phase III clinical trial as OA-modifying agent.