Article Text

PDF

Extended report
Autophagy activation by rapamycin reduces severity of experimental osteoarthritis
  1. Beatriz Caramés1,
  2. Akihiko Hasegawa1,
  3. Noboru Taniguchi1,
  4. Shigeru Miyaki1,
  5. Francisco J Blanco2,
  6. Martin Lotz1
  1. 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
  2. 2Laboratorio de Investigación Osteoarticular y del Envejecimiento, Reumatología, INIBIC–Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
  1. Correspondence to Martin Lotz, Department of Molecular and Experimental Medicine, MEM-161, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; mlotz{at}scripps.edu

Abstract

Objectives 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.

Methods 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.

Results 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.

Conclusions 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.

Statistics from Altmetric.com

Footnotes

  • Funding This study was supported by National Institutes of Health grants AG007996, AR058954, RR027577 and the Sam and Rose Stein Endowment Fund. BC was supported by postdoctoral fellowship ‘Anxeles Alvariño’, Secretaria Xeral I+D+i, Xunta de Galicia, Spain.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Institutional Animal Care and Use Committee at The Scripps Research Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.