Temsirolimus, a water-soluble mTOR inhibitor, alleviates osteoarthritic changes in human chondrocytes and mouse osteoarthritis models.

IF 2.1 4区 医学 Q3 CELL BIOLOGY
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
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引用次数: 0

Abstract

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.

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。
目的:替西莫司是一种水溶性哺乳动物雷帕霉素(mTOR)复合物靶点抑制剂,可能适用于关节内给药。本研究旨在评估关节内给药替西莫司对人软骨细胞和小鼠骨关节炎(OA)进展的治疗作用。材料和方法:采用实时聚合酶链反应、TUNEL染色检测细胞凋亡和CYTO-ID(R)染色检测细胞自噬,对体外IL-1β治疗或不治疗的人软骨细胞(正常人关节软骨细胞-膝关节细胞)进行替西莫司治疗的有益效果进行评估。通过组织和免疫组织化学分析,在体内OA模型(C57BL/6J不稳定的内侧半月板和衰老加速小鼠8 (SAMP8))中评估关节内注射替西莫司的治疗效果。结果:替西莫司可上调人软骨细胞中COL2A1和聚集蛋白(关节软骨中的一种主要蛋白聚糖)的表达。此外,替西莫司治疗恢复了IL-1β诱导的下调的COL2A1和聚集蛋白表达,同时部分降低了上调的MMP-1、MMP-13、ADAMTS-4、ADAMTS-5、IL-1β和IL-6的表达和凋亡。此外,替西莫司治疗增强了人软骨细胞的自噬活性。与对照组小鼠相比,12周龄和1岁龄手术诱导的野生型OA模型小鼠和SAMP8小鼠关节内注射替西莫司可延缓OA进展。结论:替西莫司治疗可保护人软骨细胞免受il -1β诱导的OA基因表达改变和凋亡。在小鼠OA模型和SAMP8小鼠中,关节内注射替西莫司可延缓OA进展。因此,关节内给药替西莫司是一种很有前途的治疗方法,以抑制关节软骨退化。
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来源期刊
Connective Tissue Research
Connective Tissue Research 生物-细胞生物学
CiteScore
6.60
自引率
3.40%
发文量
37
审稿时长
2 months
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.
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