{"title":"替西莫司是一种水溶性mTOR抑制剂,可减轻人软骨细胞和小鼠骨关节炎模型的骨关节炎变化。","authors":"Yuhei Otsuki, Takehiko Matsushita, Akiyoshi Mori, Nobuaki Miyaji, Tetsuya Yamamoto, Kiminari Kataoka, Shohei Sano, Naosuke Nagata, Kyohei Nishida, Kanto Nagai, Noriyuki Kanzaki, Yuichi Hoshino, Tomoyuki Matsumoto, Ryosuke Kuroda","doi":"10.1080/03008207.2025.2521404","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose/aim: </strong>Temsirolimus is a water-soluble mammalian target of rapamycin (mTOR) complex inhibitor, potentially suitable for intra-articular administration. The present study aims to evaluate the therapeutic effects of intra-articular administration of temsirolimus on human chondrocytes and osteoarthritis (OA) progression in mice.</p><p><strong>Materials and methods: </strong>The beneficial effects of temsirolimus treatment were evaluated in human chondrocytes (Normal Human Articular Chondrocyte-Knee cells) with or without treatment with IL-1β <i>in vitro</i> by real-time polymerase chain reaction, TUNEL staining for apoptosis, and CYTO-ID(R) staining for autophagy. The therapeutic effect of intra-articular injection of temsirolimus was evaluated in OA models (destabilized medial meniscus in C57BL/6J and senescence accelerated mice prone 8 (SAMP8)) <i>in vivo</i>, by histological and immunohistochemical analyses.</p><p><strong>Results: </strong>Temsirolimus treatment upregulated COL2A1 and aggrecan (a major proteoglycan in the articular cartilage) expression in human chondrocytes. In addition, temsirolimus treatment recovered IL-1β-induced down-reregulated COL2A1 and aggrecan expression, while it partially decreased upregulated MMP-1, MMP-13, ADAMTS-4, ADAMTS-5, IL-1β, and IL-6 expression and apoptosis in human chondrocytes. Further, temsirolimus treatment enhanced autophagic activity in human chondrocytes. The intra-articular injection of temsirolimus to 12-week and 1-year old wild-type surgically induced OA model mice and SAMP8 mice delayed OA progression as compared to that in the control mice.</p><p><strong>Conclusions: </strong>Temsirolimus treatment protected human chondrocytes from IL-1β-induced OA gene expression changes and apoptosis. Intra-articular injection of temsirolimus delayed OA progression in the mouse OA model and in SAMP8 mice. Thus, the intra-articular administration of temsirolimus is a promising therapeutic approach to inhibit articular cartilage degradation.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"1-15"},"PeriodicalIF":2.1000,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Temsirolimus, a water-soluble mTOR inhibitor, alleviates osteoarthritic changes in human chondrocytes and mouse osteoarthritis models.\",\"authors\":\"Yuhei Otsuki, Takehiko Matsushita, Akiyoshi Mori, Nobuaki Miyaji, Tetsuya Yamamoto, Kiminari Kataoka, Shohei Sano, Naosuke Nagata, Kyohei Nishida, Kanto Nagai, Noriyuki Kanzaki, Yuichi Hoshino, Tomoyuki Matsumoto, Ryosuke Kuroda\",\"doi\":\"10.1080/03008207.2025.2521404\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose/aim: </strong>Temsirolimus is a water-soluble mammalian target of rapamycin (mTOR) complex inhibitor, potentially suitable for intra-articular administration. The present study aims to evaluate the therapeutic effects of intra-articular administration of temsirolimus on human chondrocytes and osteoarthritis (OA) progression in mice.</p><p><strong>Materials and methods: </strong>The beneficial effects of temsirolimus treatment were evaluated in human chondrocytes (Normal Human Articular Chondrocyte-Knee cells) with or without treatment with IL-1β <i>in vitro</i> by real-time polymerase chain reaction, TUNEL staining for apoptosis, and CYTO-ID(R) staining for autophagy. The therapeutic effect of intra-articular injection of temsirolimus was evaluated in OA models (destabilized medial meniscus in C57BL/6J and senescence accelerated mice prone 8 (SAMP8)) <i>in vivo</i>, by histological and immunohistochemical analyses.</p><p><strong>Results: </strong>Temsirolimus treatment upregulated COL2A1 and aggrecan (a major proteoglycan in the articular cartilage) expression in human chondrocytes. In addition, temsirolimus treatment recovered IL-1β-induced down-reregulated COL2A1 and aggrecan expression, while it partially decreased upregulated MMP-1, MMP-13, ADAMTS-4, ADAMTS-5, IL-1β, and IL-6 expression and apoptosis in human chondrocytes. Further, temsirolimus treatment enhanced autophagic activity in human chondrocytes. The intra-articular injection of temsirolimus to 12-week and 1-year old wild-type surgically induced OA model mice and SAMP8 mice delayed OA progression as compared to that in the control mice.</p><p><strong>Conclusions: </strong>Temsirolimus treatment protected human chondrocytes from IL-1β-induced OA gene expression changes and apoptosis. Intra-articular injection of temsirolimus delayed OA progression in the mouse OA model and in SAMP8 mice. Thus, the intra-articular administration of temsirolimus is a promising therapeutic approach to inhibit articular cartilage degradation.</p>\",\"PeriodicalId\":10661,\"journal\":{\"name\":\"Connective Tissue Research\",\"volume\":\" \",\"pages\":\"1-15\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2025-06-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Connective Tissue Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/03008207.2025.2521404\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Connective Tissue Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/03008207.2025.2521404","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Temsirolimus, a water-soluble mTOR inhibitor, alleviates osteoarthritic changes in human chondrocytes and mouse osteoarthritis models.
Purpose/aim: Temsirolimus is a water-soluble mammalian target of rapamycin (mTOR) complex inhibitor, potentially suitable for intra-articular administration. The present study aims to evaluate the therapeutic effects of intra-articular administration of temsirolimus on human chondrocytes and osteoarthritis (OA) progression in mice.
Materials and methods: The beneficial effects of temsirolimus treatment were evaluated in human chondrocytes (Normal Human Articular Chondrocyte-Knee cells) with or without treatment with IL-1β in vitro by real-time polymerase chain reaction, TUNEL staining for apoptosis, and CYTO-ID(R) staining for autophagy. The therapeutic effect of intra-articular injection of temsirolimus was evaluated in OA models (destabilized medial meniscus in C57BL/6J and senescence accelerated mice prone 8 (SAMP8)) in vivo, by histological and immunohistochemical analyses.
Results: Temsirolimus treatment upregulated COL2A1 and aggrecan (a major proteoglycan in the articular cartilage) expression in human chondrocytes. In addition, temsirolimus treatment recovered IL-1β-induced down-reregulated COL2A1 and aggrecan expression, while it partially decreased upregulated MMP-1, MMP-13, ADAMTS-4, ADAMTS-5, IL-1β, and IL-6 expression and apoptosis in human chondrocytes. Further, temsirolimus treatment enhanced autophagic activity in human chondrocytes. The intra-articular injection of temsirolimus to 12-week and 1-year old wild-type surgically induced OA model mice and SAMP8 mice delayed OA progression as compared to that in the control mice.
Conclusions: Temsirolimus treatment protected human chondrocytes from IL-1β-induced OA gene expression changes and apoptosis. Intra-articular injection of temsirolimus delayed OA progression in the mouse OA model and in SAMP8 mice. Thus, the intra-articular administration of temsirolimus is a promising therapeutic approach to inhibit articular cartilage degradation.
期刊介绍:
The aim of Connective Tissue Research is to present original and significant research in all basic areas of connective tissue and matrix biology.
The journal also provides topical reviews and, on occasion, the proceedings of conferences in areas of special interest at which original work is presented.
The journal supports an interdisciplinary approach; we present a variety of perspectives from different disciplines, including
Biochemistry
Cell and Molecular Biology
Immunology
Structural Biology
Biophysics
Biomechanics
Regenerative Medicine
The interests of the Editorial Board are to understand, mechanistically, the structure-function relationships in connective tissue extracellular matrix, and its associated cells, through interpretation of sophisticated experimentation using state-of-the-art technologies that include molecular genetics, imaging, immunology, biomechanics and tissue engineering.