Deletion of the transforming growth factor ? receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.

ABSTRACT: While 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.TGF? receptor type II (TGF?RII)-conditional knockout (KO) (TGF?RII(Col2ER)) mice were generated by breeding TGF?RII(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, TGF?RII/matrix metalloproteinase 13 (MMP-13)- and TGF?RII/ADAMTS-5-double-KO mice were generated and analyzed.Inhibition 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 TGF?RII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGF? signaling. Treatment of TGF?RII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression.Mmp13 and Adamts5 are critical downstream target genes involved in the TGF? signaling pathway during the development of OA.

SUBMITTER: Shen J 

PROVIDER: S-EPMC3928444 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature