Degrasyn alleviates osteoarthritis by blocking macrophagic pyroptosis via suppressing NLRP3/GSDMD signaling pathway and protecting chondrocytes

Shujun Xie; Linqiao Wang; Congcong Lu; Hao Chen; Yi Ding; Xu Jian; Zhen Zhang; Liulong Zhu

doi:10.1016/j.cellsig.2024.111220

Degrasyn alleviates osteoarthritis by blocking macrophagic pyroptosis via suppressing NLRP3/GSDMD signaling pathway and protecting chondrocytes

Cell Signal. 2024 May 11:111220. doi: 10.1016/j.cellsig.2024.111220. Online ahead of print.

Authors

Shujun Xie¹, Linqiao Wang², Congcong Lu³, Hao Chen⁴, Yi Ding⁴, Xu Jian⁵, Zhen Zhang⁶, Liulong Zhu⁷

Affiliations

¹ Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Cancer Center, Hangzhou 310006, China.
² Department of Pediatrics, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province 31000, China.
³ Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province 31000, China; The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
⁴ Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province 31000, China.
⁵ Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, PR China.
⁶ Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province 31000, China. Electronic address: zhangzhen9714@163.con.
⁷ Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province 31000, China. Electronic address: zhuliulong@zju.edu.cn.

PMID: 38740234
DOI: 10.1016/j.cellsig.2024.111220

Abstract

Synovitis and cartilage destruction are crucial characteristics of osteoarthritis (OA). Inflammatory cytokines, such as IL-1β, are secreted by synovial macrophages, leading to cartilage destruction. Pyroptosis is a lytic form of programmed cell death, which could be triggered by the NLRP3 inflammasome of macrophages. Pyroptosis promotes the secretion of IL-1β and is supposed as a potential biomarker for OA. However, the function of Pyroptosis and NLRP3 inflammasome and its regulatory mechanism for activation is unclear in OA. In this study, we found that Degrasyn could alleviate the GSDMD-mediated pyroptosis of macrophages and the release of IL-1β, caspase-1, and LDH. Furthermore, it selectively impedes the form of ASC oligomer and speckle to effectively suppress the NLRP3 inflammasome during its assembly phase. Notably, Degrasyn exhibited potential chondroprotective effects in a co-culture system. Additionally, these results also indicate that Degrasyn mitigates synovitis and cartilage damage in a murine model of destabilization of the medial meniscus (DMM)-induced OA. In summary, Degrasyn emerges as a promising pharmaceutical agent for synovitis, paving the way for innovative therapeutic approaches to OA. Our findings underscore the potential of Degrasyn as a viable candidate for OA therapeutics, demonstrating its ability to regulate pyroptosis and NLRP3 inflammasome activation.

Keywords: Chondrocytes; Degrasyn; Macrophages; NLRP3 inflammasome; Osteoarthritis; Pyroptosis.