| First Author | Shen J | Year | 2013 |
| Journal | Arthritis Rheum | Volume | 65 |
| Issue | 12 | Pages | 3107-19 |
| PubMed ID | 23982761 | Mgi Jnum | J:310045 |
| Mgi Id | MGI:6760100 | Doi | 10.1002/art.38122 |
| Citation | Shen J, et al. (2013) Deletion of the transforming growth factor beta receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum 65(12):3107-19 |
| abstractText | OBJECTIVE: While transforming growth factor beta (TGFbeta) signaling plays a critical role in chondrocyte metabolism, the TGFbeta 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 TGFbeta signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFbeta signaling. METHODS: TGFbeta receptor type II (TGFbetaRII)-conditional knockout (KO) (TGFbetaRII(Col2ER)) mice were generated by breeding TGFbetaRII(flox/flox) mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFbeta signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFbeta signaling, TGFbetaRII/matrix metalloproteinase 13 (MMP-13)- and TGFbetaRII/ADAMTS-5-double-KO mice were generated and analyzed. RESULTS: Inhibition of TGFbeta 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 TGFbetaRII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGFbeta signaling. Treatment of TGFbetaRII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression. CONCLUSION: Mmp13 and Adamts5 are critical downstream target genes involved in the TGFbeta signaling pathway during the development of OA. |
