Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
The Second School of Medicine, Wenzhou Medical University, China.
Biochem Biophys Res Commun. 2021 May 14;553:119-125. doi: 10.1016/j.bbrc.2021.03.055. Epub 2021 Mar 22.
Excessive activation of inflammation in chondrocyte has been considered to be a major reason cause of cellular death and degeneration in osteoarthritis (OA) development. The NLRP3 inflammasome-mediated pyroptosis pathway is closely related to inflammation regulation. This research was conducted to confirm whether NLRP3 expression and activity are impacted in the development of OA and to detect the role of CY-09, a selective and direct inhibitor of NLRP3 in the in vitro and in vivo models of OA. Our findings corroborated that the expression of NLRP3 is stimulated in OA cartilage. CY-09 can maintain extracellular matrix (ECM) homeostasis and regulate inflammation in TNF-α treated chondrocytes via inhibition of NLRP3 inflammasome-mediated pyroptosis. Moreover, the chondrocyte protective effects of CY-09 were further confirmed in vivo in a DMM-induced OA model. In conclusion, our research indicates that experimental OA activated the NLRP3 activity, and pharmacological inhibition of NLRP3 inflammasome activation by CY-09 protects chondrocytes against inflammation and attenuates OA development.
软骨细胞中炎症的过度激活被认为是骨关节炎（OA）发展过程中细胞死亡和退化的主要原因。NLRP3 炎性小体介导热激细胞程序性细胞死亡（pyroptosis）途径与炎症调节密切相关。本研究旨在确认 NLRP3 的表达和活性是否在 OA 的发展中受到影响，并检测 NLRP3 的选择性和直接抑制剂 CY-09 在 OA 的体外和体内模型中的作用。我们的研究结果证实，NLRP3 在 OA 软骨中的表达受到刺激。CY-09 通过抑制 NLRP3 炎性小体介导的 pyroptosis 来维持细胞外基质（ECM）的稳态并调节 TNF-α 处理的软骨细胞中的炎症。此外，在 DMM 诱导的 OA 模型中，进一步在体内证实了 CY-09 对软骨细胞的保护作用。总之，我们的研究表明，实验性 OA 激活了 NLRP3 活性，而 CY-09 通过抑制 NLRP3 炎性小体的激活对 NLRP3 炎性小体的药理学抑制可保护软骨细胞免受炎症并减轻 OA 的发展。
