Zhuang Qian , Jie Xu , Lei Zhang , Zheng Miao , Ziyan Lv , Hongwei Ji , Qian Deng , Zhuangwei Lv , Heqin Zhan , Yang Yu , Zichuan Liu , Wenjie Ren
{"title":"Muscone通过Nrf2/NF-κB轴抑制M1巨噬细胞极化,保护软骨细胞,改善骨关节炎进展","authors":"Zhuang Qian , Jie Xu , Lei Zhang , Zheng Miao , Ziyan Lv , Hongwei Ji , Qian Deng , Zhuangwei Lv , Heqin Zhan , Yang Yu , Zichuan Liu , Wenjie Ren","doi":"10.1016/j.taap.2025.117494","DOIUrl":null,"url":null,"abstract":"<div><div>Osteoarthritis (OA) is a common and chronic joint condition marked by the deterioration of cartilage, osteophyte formation, and synovial inflammation (synovitis), severely impairing physical function and quality of life. The synovitis is crucial for initiation and exacerbation of OA. Muscone, the main bioactive compound found in musk, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. Nevertheless, it is still uncertain whether Muscone alleviates the progression of OA by suppressing inflammation. Our research investigated how Muscone affected M1 macrophage polarization and joint inflammation in vitro, as well as its effects on OA progression in vivo. Our findings showed that Muscone significantly inhibited pro-inflammatory cytokine secretion and M1 polarization in LPS-induced RAW264.7 macrophages. Moreover, Muscone suppressed synovitis by impeding pro-inflammatory and M1-related factors in synovium of OA mice. Mechanistic investigations revealed Muscone directly bound Nrf2 and promoted its nuclear translation in LPS-induced RAW264.7 cells, while also simultaneously suppressing the phosphorylation of P65 and IκBα within the NF-κB signaling pathway. Moreover, the pharmacological blockade of Nrf2 partially mitigated the influence of Muscone on LPS-triggered M1 macrophage polarization and the NF-κB pathway. Furthermore, Muscone slowed down the degeneration of articular cartilage in OA mice by promoting chondrocyte anabolism and simultaneously inhibiting inflammation, catabolic processes, and apoptosis of chondrocytes. Overall, our findings indicate that Muscone mitigates the advancement of OA through the inhibition of M1 macrophage polarization and the protection of chondrocytes, thus highlighting its potential as a therapeutic candidate for OA treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117494"},"PeriodicalIF":3.4000,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Muscone ameliorates osteoarthritis progression by inhibiting M1 macrophages polarization via Nrf2/NF-κB axis and protecting chondrocytes\",\"authors\":\"Zhuang Qian , Jie Xu , Lei Zhang , Zheng Miao , Ziyan Lv , Hongwei Ji , Qian Deng , Zhuangwei Lv , Heqin Zhan , Yang Yu , Zichuan Liu , Wenjie Ren\",\"doi\":\"10.1016/j.taap.2025.117494\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Osteoarthritis (OA) is a common and chronic joint condition marked by the deterioration of cartilage, osteophyte formation, and synovial inflammation (synovitis), severely impairing physical function and quality of life. The synovitis is crucial for initiation and exacerbation of OA. Muscone, the main bioactive compound found in musk, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. Nevertheless, it is still uncertain whether Muscone alleviates the progression of OA by suppressing inflammation. Our research investigated how Muscone affected M1 macrophage polarization and joint inflammation in vitro, as well as its effects on OA progression in vivo. Our findings showed that Muscone significantly inhibited pro-inflammatory cytokine secretion and M1 polarization in LPS-induced RAW264.7 macrophages. Moreover, Muscone suppressed synovitis by impeding pro-inflammatory and M1-related factors in synovium of OA mice. Mechanistic investigations revealed Muscone directly bound Nrf2 and promoted its nuclear translation in LPS-induced RAW264.7 cells, while also simultaneously suppressing the phosphorylation of P65 and IκBα within the NF-κB signaling pathway. Moreover, the pharmacological blockade of Nrf2 partially mitigated the influence of Muscone on LPS-triggered M1 macrophage polarization and the NF-κB pathway. Furthermore, Muscone slowed down the degeneration of articular cartilage in OA mice by promoting chondrocyte anabolism and simultaneously inhibiting inflammation, catabolic processes, and apoptosis of chondrocytes. Overall, our findings indicate that Muscone mitigates the advancement of OA through the inhibition of M1 macrophage polarization and the protection of chondrocytes, thus highlighting its potential as a therapeutic candidate for OA treatment.</div></div>\",\"PeriodicalId\":23174,\"journal\":{\"name\":\"Toxicology and applied pharmacology\",\"volume\":\"503 \",\"pages\":\"Article 117494\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-07-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology and applied pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0041008X25002704\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X25002704","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Muscone ameliorates osteoarthritis progression by inhibiting M1 macrophages polarization via Nrf2/NF-κB axis and protecting chondrocytes
Osteoarthritis (OA) is a common and chronic joint condition marked by the deterioration of cartilage, osteophyte formation, and synovial inflammation (synovitis), severely impairing physical function and quality of life. The synovitis is crucial for initiation and exacerbation of OA. Muscone, the main bioactive compound found in musk, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. Nevertheless, it is still uncertain whether Muscone alleviates the progression of OA by suppressing inflammation. Our research investigated how Muscone affected M1 macrophage polarization and joint inflammation in vitro, as well as its effects on OA progression in vivo. Our findings showed that Muscone significantly inhibited pro-inflammatory cytokine secretion and M1 polarization in LPS-induced RAW264.7 macrophages. Moreover, Muscone suppressed synovitis by impeding pro-inflammatory and M1-related factors in synovium of OA mice. Mechanistic investigations revealed Muscone directly bound Nrf2 and promoted its nuclear translation in LPS-induced RAW264.7 cells, while also simultaneously suppressing the phosphorylation of P65 and IκBα within the NF-κB signaling pathway. Moreover, the pharmacological blockade of Nrf2 partially mitigated the influence of Muscone on LPS-triggered M1 macrophage polarization and the NF-κB pathway. Furthermore, Muscone slowed down the degeneration of articular cartilage in OA mice by promoting chondrocyte anabolism and simultaneously inhibiting inflammation, catabolic processes, and apoptosis of chondrocytes. Overall, our findings indicate that Muscone mitigates the advancement of OA through the inhibition of M1 macrophage polarization and the protection of chondrocytes, thus highlighting its potential as a therapeutic candidate for OA treatment.
期刊介绍:
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.