Deletion of the Transforming Growth Factor β Receptor Type II Gene in Articular Chondrocytes Leads to a Progressive Osteoarthritis-like Phenotype in Mice

ObjectiveWhile transforming growth factor (TGF) signaling plays a critical role in chondrocyte metabolism, the TGF 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 TGF signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGF signaling. MethodsTGF receptor type II (TGFRII)-conditional knockout (KO) (TGFRII(Col2ER)) mice were generated by breeding TGFRII(flox/flox) mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGF signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGF signaling, TGFRII/matrix metalloproteinase 13 (MMP-13)- and TGFRII/ADAMTS-5-double-KO mice were generated and analyzed. ResultsInhibition of TGF 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 TGFRII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGF signaling. Treatment of TGFRII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression. ConclusionMmp13 and Adamts5 are critical downstream target genes involved in the TGF signaling pathway during the development of OA.