title: Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.
abstract: OBJECTIVE
  While transforming growth factor β (TGFβ) signaling plays a critical role in chondrocyte metabolism, the TGFβ signaling pathways and target genes involved in cartilage homeostasis and the development of osteoarthritis (OA) remain unclear. Using an in vitro cell culture method and an in vivo mouse genetic approach, we undertook this study to investigate TGFβ signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling.
  
  
  METHODS
  TGFβ receptor type II (TGFβRII)-conditional knockout (KO) (TGFβRII(Col2ER)) mice were generated by breeding TGFβRII(flox/flox) mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFβ signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling, TGFβRII/matrix metalloproteinase 13 (MMP-13)- and TGFβRII/ADAMTS-5-double-KO mice were generated and analyzed.
  
  
  RESULTS
  Inhibition of TGFβ signaling (deletion of the Tgfbr2 gene in chondrocytes) resulted in up-regulation of Runx2, Mmp13, and Adamts5 expression in articular cartilage tissue and progressive OA development in TGFβRII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGFβ signaling. Treatment of TGFβRII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression.
  
  
  CONCLUSIONS
  Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA.
authors: Rush University Medical Center, Chicago, Illinois; University of Rochester School of Medicine, Rochester, New York.
authors: Jie
authors: J
authors: Shen
authors: Jia
authors: J
authors: Li
authors: Baoli
authors: B
authors: Wang
authors: Hongting
authors: H
authors: Jin
authors: Meina
authors: M
authors: Wang
authors: Yejia
authors: Y
authors: Zhang
authors: Yunzhi
authors: Y
authors: Yang
authors: Hee-Jeong
authors: HJ
authors: Im
authors: Regis
authors: R
authors: O'Keefe
authors: Di
authors: D
authors: Chen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D018125:Receptors, Transforming Growth Factor beta; C493726:Runx1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D053509:Matrix Metalloproteinase 13
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