Open AccessDeletion of the Transforming Growth Factor β Receptor Type II Gene in Articular Chondrocytes Leads to a Progressive Osteoarthritis‐like Phenotype in Mice
Author(s) -
Shen Jie,
Li Jia,
Wang Baoli,
Jin Hongting,
Wang Meina,
Zhang Yejia,
Yang Yunzhi,
Im HeeJeong,
O'Keefe Regis,
Chen Di
Publication year - 2013
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.38122
Subject(s) - transforming growth factor , chondrocyte , conditional gene knockout , transforming growth factor beta , signal transduction , microbiology and biotechnology , chondrogenesis , type ii collagen , cartilage , osteoarthritis , phenotype , cancer research , biology , chemistry , gene , pathology , medicine , anatomy , genetics , mesenchymal stem cell , alternative medicine
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. Conclusion Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA.