title: 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.
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.
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands Integrated Research of Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, Netherlands.
authors.forename: Nils
authors.initials: N
authors.lastname: Bomer
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium.
authors.forename: Frederique M F
authors.initials: FM
authors.lastname: Cornelis
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.
authors.forename: Yolande F M
authors.initials: YF
authors.lastname: Ramos
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: den Hollander
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: Storms
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Lakenberg
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands Integrated Research of Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, Netherlands The Netherlands Genomics Initiative, sponsored by the NCHA, Leiden-Rotterdam, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative, sponsored by the NCHA, Leiden-Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik J L
authors.initials: RJ
authors.lastname: Lories
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D007453:Iodide Peroxidase / Q000235:genetics*; D007719:Knee Joint / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010805:Physical Conditioning, Animal; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013314:Stress, Mechanical; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D012333:RNA, Messenger; D000097564:Iodothyronine Deiodinase Type II
keywords: Disease Activity; Knee Osteoarthritis; Osteoarthritis; Treatment