Article Text

OP0312 Diabetes-Accelerated Experimental Osteoarthritis Is Prevented by Autophagy Activation
  1. B. Carames1,
  2. M. Ribeiro1,2,
  3. P. Lopez de Figueroa1,
  4. U. Nogueira-Recalde1,
  5. A. Centeno3,
  6. A.F. Mendes2,
  7. F.J. Blanco4
  1. 1Cartilage Biology Group. Rheumatology Division, Biomedical Research Institute of A Coruña, a Coruña, Spain
  2. 2Centre for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
  3. 3Unidad de Cirugía Experimental
  4. 4Rheumatology Division, Biomedical research Institute of A Coruña, a Coruña, Spain


Background Type 2 Diabetes (T2D) is a risk factor for Osteoarthritis (OA) (1). Autophagy, an essential mechanism in articular cartilage, is defective in T2D and OA (2). However, how T2D may influence OA progression is still unknown.

Objectives We aimed to determine how diabetes affects cartilage integrity and whether pharmacological activation of autophagy has disease-modifying efficacy in diabetic mice with OA.

Methods Experimental OA was performed in the right knee of 9 weeks-old C57Bl/6 male mice (Lean group, N=8) and of 9 weeks-old B6.BKS (D)-Leprdb male mice (db/db group, N=16) by transection of medial meniscotibial and medial collateral ligaments. Left knee was employed as control knee. Rapamycin (2 mg/kg weight/day) or Vehicle (dimethyl sulphoxide) were administered intraperitoneally 3 times a week for 10 weeks. Body weight and fasting blood glucose levels were monitorized weekly. Insulin levels in plasma were determined by ELISA at the end of the study. Histopathology in articular cartilage and synovium was evaluated by using semiquantitative scoring and synovitis grading systems, respectively. Immunohistochemistry was employed to evaluate the effect of diabetes and Rapamycin on cartilage integrity and OA biomarkers.

Results Diabetic mice have increased body weight, fasting blood glucose levels and insulin levels compared to lean mice. Importantly, Rapamycin treated mice have significantly reduced body weight and blood glucose and insulin compared to control db/db mice. Moreover, rapamycin treatment significantly reduced the phosphorylation of rpS6, a direct target of mTOR and increased phosphorylation of AMPK. The results indicated that cartilage damage was significantly increased in db/db mice compared to lean group after surgical induction of OA, while no differences are observed in the control knee. mTOR inhibition protects against surgical-induced OA in db/db mice joints. Cartilage damage and OA severity was significantly reduced in the treated group. This reduction was accompanied with a significant reduction in synovium inflammation and in the expression of OA biomarkers, such as MMP-13 and ADAMTS-5 and decreased IL-12 levels. Furthermore, LC3 lipidation, a marker of autophagosome formation, was increased and cartilage cellularity was maintained after treatment, suggesting that autophagy activation protects chondrocytes against death.

Conclusions Our findings indicate that diabetic mice exhibit accelerated-joint damage after experimental OA, and that autophagy activation might be an effective therapy for diabetes-accelerated OA.

  1. Berenbaum F. Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype. Postgrad Med J 2012.88:240–2.

  2. Levine B and Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008. 132:27–42.

Acknowledgement This study was supported by Instituto de Salud Carlos III-Ministerio de Economía y Competitividad, Spain-CP11/00095 and Fondo Europeo de Desarrollo Regional (FEDER). Madalena Ribeiro was supported by Fundo Social Europeu (FSE), through “Programa Operacional Potencial Humano” (POPH), and national funds via FCT – Fundaçao Portuguesa para a Ciencia e a Tecnologia under the PhD fellowship, SFRH/BD/78188/2011.

Disclosure of Interest None declared

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