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

J Shen, J Li, B Wang, H Jin, M Wang… - Arthritis & …, 2013 - Wiley Online Library
J Shen, J Li, B Wang, H Jin, M Wang, Y Zhang, Y Yang, HJ Im, R O'Keefe, D Chen
Arthritis & Rheumatism, 2013Wiley Online Library
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 …
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) (TGFβRIICol2ER) mice were generated by breeding TGFβRIIflox/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 TGFβRIICol2ER mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA‐like phenotype induced by the loss of TGFβ signaling. Treatment of TGFβRIICol2ER 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.
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