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

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.

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.

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.

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.