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已发表论文
信号素 6D 通过抑制 NLRP3 炎性小体激活和内质网应激缓解骨关节炎
Authors Zhang W , Li C, Yao J , Xu Z, Huang Y, Lu Y, Lin X, Guo Z, Zhou X
Received 27 March 2025
Accepted for publication 28 September 2025
Published 7 October 2025 Volume 2025:18 Pages 13909—13924
DOI https://doi.org/10.2147/JIR.S525953
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Ujjwol Risal
Wenchao Zhang,1,* Chongrui Li,2,* Jiapei Yao,3 Zhonghua Xu,1 Yong Huang,3 Yaojun Lu,3 Xiaolong Lin,4 Zili Guo,5,6 Xindie Zhou3,7
1Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, 213200, People’s Republic of China; 2School of Stomatology, Jingchu University of Technology, Jingmen, 448000, People’s Republic of China; 3Department of Orthopedics, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou, 213000, People’s Republic of China; 4Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, People’s Republic of China; 5Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China; 6Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China; 7Department of Orthopedics, Gonghe County Hospital of Traditional Chinese Medicine, Hainan Tibetan Autonomous Prefecture, Qinghai, 811800, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zili Guo, Email guozili_cn@163.com Xindie Zhou, Email zhouxindie@njmu.edu.cn
Objective: Osteoarthritis (OA) is a degenerative joint disease that affects over 500 million individuals globally, characterized by the degradation of cartilage, subchondral bone sclerosis, and synovitis. A key factor in the progression of OA is synovial inflammation, which is driven by macrophage polarization and inflammasome activation. This inflammation exacerbates cartilage degradation, creating a vicious cycle that accelerates disease progression. Targeting macrophage activity presents a promising therapeutic strategy to alleviate the symptoms and progression of OA.
Methods: To investigate the role of SEMA6D in macrophage polarization and its potential therapeutic implications for OA, we conducted transcriptomic analysis to explore its regulatory functions. In vitro experiments were performed to assess the effects of SEMA6D overexpression on the expression of ASC and NLRP3, as well as on macrophage (RAW264.7) polarization toward the pro-inflammatory M1 phenotype. In vivo studies were conducted using an OA rat model to evaluate the influence of SEMA6D overexpression on synovial macrophage polarization and the levels of inflammatory mediators, including IL-1β and IL-6.
Results: Our transcriptomic analysis indicated that SEMA6D plays a regulatory role in macrophage polarization. Overexpression of SEMA6D resulted in the downregulation of ASC and NLRP3, effectively inhibiting the polarization of macrophages toward the M1 phenotype and downregulate the expression levels of iNOS and IL-6 by more than twofold. In the DMM rat model, SEMA6D overexpression significantly reduced the polarization of synovial macrophages to the M1 phenotype, leading to lower levels of inflammatory mediators such as IL-1β and IL-6, and mitigating cartilage degeneration.
Conclusion: SEMA6D exerts a protective effect against OA by attenuating synovial macrophage-mediated inflammatory responses through the inhibition of NLRP3 inflammasome activation and endoplasmic reticulum stress.
Keywords: osteoarthritis, NLRP3, inflammasome, SEMA6D, macrophage
1Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu, 213200, People’s Republic of China; 2School of Stomatology, Jingchu University of Technology, Jingmen, 448000, People’s Republic of China; 3Department of Orthopedics, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou, 213000, People’s Republic of China; 4Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, People’s Republic of China; 5Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China; 6Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China; 7Department of Orthopedics, Gonghe County Hospital of Traditional Chinese Medicine, Hainan Tibetan Autonomous Prefecture, Qinghai, 811800, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zili Guo, Email guozili_cn@163.com Xindie Zhou, Email zhouxindie@njmu.edu.cn
Objective: Osteoarthritis (OA) is a degenerative joint disease that affects over 500 million individuals globally, characterized by the degradation of cartilage, subchondral bone sclerosis, and synovitis. A key factor in the progression of OA is synovial inflammation, which is driven by macrophage polarization and inflammasome activation. This inflammation exacerbates cartilage degradation, creating a vicious cycle that accelerates disease progression. Targeting macrophage activity presents a promising therapeutic strategy to alleviate the symptoms and progression of OA.
Methods: To investigate the role of SEMA6D in macrophage polarization and its potential therapeutic implications for OA, we conducted transcriptomic analysis to explore its regulatory functions. In vitro experiments were performed to assess the effects of SEMA6D overexpression on the expression of ASC and NLRP3, as well as on macrophage (RAW264.7) polarization toward the pro-inflammatory M1 phenotype. In vivo studies were conducted using an OA rat model to evaluate the influence of SEMA6D overexpression on synovial macrophage polarization and the levels of inflammatory mediators, including IL-1β and IL-6.
Results: Our transcriptomic analysis indicated that SEMA6D plays a regulatory role in macrophage polarization. Overexpression of SEMA6D resulted in the downregulation of ASC and NLRP3, effectively inhibiting the polarization of macrophages toward the M1 phenotype and downregulate the expression levels of iNOS and IL-6 by more than twofold. In the DMM rat model, SEMA6D overexpression significantly reduced the polarization of synovial macrophages to the M1 phenotype, leading to lower levels of inflammatory mediators such as IL-1β and IL-6, and mitigating cartilage degeneration.
Conclusion: SEMA6D exerts a protective effect against OA by attenuating synovial macrophage-mediated inflammatory responses through the inhibition of NLRP3 inflammasome activation and endoplasmic reticulum stress.
Keywords: osteoarthritis, NLRP3, inflammasome, SEMA6D, macrophage