Article

Autophagy activation by rapamycin reduces severity of experimental osteoarthritis

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
Annals of the rheumatic diseases (Impact Factor: 10.38). 11/2011; 71(4):575-81. DOI: 10.1136/annrheumdis-2011-200557
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ABSTRACT Osteoarthritis is associated with cell death and extracellular matrix degradation in articular cartilage. Autophagy is an essential cellular homeostasis mechanism that was found to be deficient in ageing and osteoarthritic cartilage. This study determined whether pharmacological inhibition of the mammalian target of rapamycin (mTOR), a key inhibitor of autophagy, has disease-modifying activity in experimental osteoarthritis.
Experimental osteoarthritis was induced by transection of the medial meniscotibial ligament and the medial collateral ligament in 2-month-old C57Bl/6 mice (n=36). Rapamycin (1 mg/kg weight/day) (n=18 mice) or dimethyl sulphoxide vehicle control (n=18 mice) was administered intraperitoneally for 10 weeks. Histopathological changes in articular cartilage and synovium were examined by using semiquantitative scoring systems. Rapamycin effects on mTOR signalling, autophagy, cartilage homeostasis and inflammation were analysed by immunohistochemistry and immunofluorescence staining.
Rapamycin affected the mTOR signalling pathway in mouse knee joints as indicated by the inhibition of ribosomal protein S6 phosphorylation, a target of mTOR and activation of LC3, a main marker of autophagy. The severity of cartilage degradation was significantly (p<0.01) reduced in the rapamycin-treated group compared with the control group and this was associated with a significant (p<0.05) decrease in synovitis. Rapamycin treatment also maintained cartilage cellularity and decreased ADAMTS-5 and interleukin-1β expression in articular cartilage.
These results suggest that rapamycin, at least in part by autophagy activation, reduces the severity of experimental osteoarthritis. Pharmacological activation of autophagy may be an effective therapeutic approach for osteoarthritis.

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Available from: Martin Lotz, Aug 16, 2015
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    • "Alternatively, mTOR (mammalian target of rapamycin) is considered a key regulator of cell growth and proliferation [15], and its expression has been reported both in fetal chondrocytes in animal studies [16] [17] [18] and in human articular chondrocytes [19]. Moreover, treatment of mice with the mTOR inhibitor rapamycin or its analogs, has been recently shown to reduce the severity of experimental osteoarthritis [20] [21] and inflammatory arthritis [19] [22]. "
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    ABSTRACT: The gene expression of mTOR, autophagy-related ULK1, caspase 3, CDK-inhibitor p21, and TNF α was measured in the peripheral blood of osteoarthritic (OA) patients at different stages of the disease aiming to establish a gene expression profile that might indicate the activity of the disease and joint destruction. Whole blood of 65 OA outpatients, 27 end-stage OA patients, 27 healthy volunteers, and knee articular cartilages of 28 end-stage OA patients and 26 healthy subjects were examined. OA outpatients were subjected to clinical testing, ultrasonography, and radiographic and WOMAC scoring. Protein levels of p70-S6K, p21, and caspase 3 were quantified by ELISA. Gene expression was measured using real-time RT-PCR. Upregulation of mTOR gene expression was observed in PBMCs of 42 OA outpatients ("High mTOR expression subset") and in PBMCs and articular cartilages of all end-stage OA patients. A positive correlation between mTOR gene expression in PBMCs and cartilage was observed in the end-stage OA patients. 23 OA outpatients in the "Low mTOR expression subset" exhibited significantly lower mTOR gene expression in PBMCs compared to healthy controls. These "Low mTOR" subset subjects experienced significantly more pain upon walking, and standing and increased total joint stiffness versus "High mTOR" subset, while the latter more often exhibited synovitis. The protein concentrations of p70-S6K, p21, and caspase 3 in PBMCs were significantly lower in the "Low" subset versus "High" subset and end-stage subjects. Increases in the expression of mTOR in PBMCs of OA patients are related to disease activity, being associated with synovitis more than with pain.
    06/2013; 2013:461486. DOI:10.1155/2013/461486
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    • "INHIBITION OF PI3K/Akt/mTOR IN OSTEOARTHRITIS mTOR inhibitor has been shown to increase autophagy in several cell types [Sabers et al., 1995; Shigemitsu et al., 1999]. Recently, rapamycin has also been demonstrated to reduce autophagy of chondrocytes in an osteoarthritis animal model [Sasaki et al., 2012; Carames et al., 2012]. Rapamycin is more effective than PI3K specific inhibitor Ly294002 because mTOR is also activated by MAPK pathway, AMPK and serum amino acids. "
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    ABSTRACT: Osteoarthristis is characterised by degenerative alterations of articular cartilage including both the degradation of extracellular matrix and the death of chondrocytes. The PI3K/Akt pathway has been demonstrated to involve in both processes. Inhibition of NF-κB reduces the degradation of extracellular matrix via decreased Matrix metalloproteinases production while inhibition of mTOR increased autophagy to reduce chondrocyte death. However, mTOR feedback inhibits the activity of the PI3K/Akt pathway and inhibition of mTOR could result in increased activity of the PI3K/Akt/NF-κB pathway. We proposed that the use of dual inhibitors of PI3K and mTOR could be a promising approach to more efficiently inhibit the PI3K/Akt pathway than rapamycin or PI3K inhibitor alone and produce better treatment outcome. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 02/2013; 114(2). DOI:10.1002/jcb.24362 · 3.37 Impact Factor
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