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The effect of forced exercise on knee joints in Dio2−/− mice: type II iodothyronine deiodinase-deficient mice are less prone to develop OA-like cartilage damage upon excessive mechanical stress
  1. Nils Bomer1,2,
  2. Frederique M F Cornelis3,
  3. Yolande FM Ramos1,
  4. Wouter den Hollander1,
  5. Lies Storms3,
  6. Ruud van der Breggen1,
  7. Nico Lakenberg1,
  8. P Eline Slagboom1,2,4,
  9. Ingrid Meulenbelt1,4,
  10. Rik JL Lories3,5
  1. 1Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands
  2. 2Integrated Research of Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, Netherlands
  3. 3Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium
  4. 4The Netherlands Genomics Initiative, sponsored by the NCHA, Leiden-Rotterdam, The Netherlands
  5. 5Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium
  1. Correspondence to Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, LUMC Post-zone S-05-P, P.O. Box 9600, Leiden 2300 RC, The Netherlands; n.bomer{at}lumc.nl

Abstract

Objective To further explore deiodinase iodothyronine type 2 (DIO2) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of Dio2 deficiency.

Methods Wild-type and C57BL/6-Dio2−/− -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein–protein interactions.

Results In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change ≥1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1), supporting the use of forced running as an OA model in mice. Dio2-deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes.

Conclusions Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of Dio2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the Dio2 knockout (eg, Gnas) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr). These data further support DIO2 activity as a therapeutic target in OA.

  • Osteoarthritis
  • Knee Osteoarthritis
  • Disease Activity
  • Treatment

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