title: Deiodinase 2 upregulation demonstrated in osteoarthritis patients cartilage causes cartilage destruction in tissue-specific transgenic rats.
abstract: OBJECTIVE
  Chondrocyte hypertrophy followed by cartilage destruction is a crucial step for osteoarthritis (OA) development, however, the underlying mechanism remains largely unknown. The objectives of this study are to identify the gene that may cause cartilage hypertrophy and to elucidate its role on OA pathogenesis.
  
  
  METHODS
  Gene expression profiles of cartilages from OA patients and normal subjects were examined by microarray analysis. Expression of deiodinases, enzymes for regulation of triiodothyronine (T3) biosynthesis, in human and rat articular cartilage (AC) were examined by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Rat ACs and chondrocytes were treated with T3 to investigate its role on chondrocyte hypertrophy and inflammatory reaction. Cartilage-specific Type II deiodinase (DIO2) transgenic rats were generated using bacterial artificial chromosome harboring the entire rat Col2a1 and human DIO2 gene. An experimental OA model was created in the animal to examine the role of DIO2 on cartilage degeneration.
  
  
  RESULTS
  DIO2 is highly expressed in OA patient AC compared to normal control. In rat AC, DIO2 is specifically expressed among deiodinases and dominantly expressed the same as in brown adipose tissue. T3 induces hypertrophic markers in articular chondrocyte and cartilage explant culture, and enhances the effect of IL-1α on induction of cartilage degrading enzymes. Importantly, cartilage-specific DIO2 transgenic rats are more susceptible to knee joint destabilization and develop severe AC destruction.
  
  
  CONCLUSIONS
  Our findings demonstrate that upregulated expression of DIO2 in OA patient cartilage might be responsible for OA pathogenesis by enhancing the chondrocyte hypertrophy and inflammatory response.
authors.affiliation: Frontier Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan. nagase.hiroyuki.z8@daiichisankyo.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: Y
authors.initials: Y
authors.lastname: Nagasawa
authors.forename: Y
authors.initials: Y
authors.lastname: Tachida
authors.forename: S
authors.initials: S
authors.lastname: Sakakibara
authors.forename: J
authors.initials: J
authors.lastname: Okutsu
authors.forename: N
authors.initials: N
authors.lastname: Suematsu
authors.forename: S
authors.initials: S
authors.lastname: Arita
authors.forename: K
authors.initials: K
authors.lastname: Shimada
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D016022:Case-Control Studies; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism; D007453:Iodide Peroxidase / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D053582:Interleukin-1alpha; D014284:Triiodothyronine; D007453:Iodide Peroxidase