Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.
Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice.
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DOI：
10.1002/art.38122
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发表时间：
2013-12
影响因子：
--
通讯作者：
Chen, Di
中科院分区：
文献类型：
--
作者：
Shen, Jie;Li, Jia;Wang, Baoli;Jin, Hongting;Wang, Meina;Zhang, Yejia;Yang, Yunzhi;Im, Hee-Jeong;O'Keefe, Regis;Chen, Di
虽然转化生长因子β（transforming growth factor β，TGFβ）信号在软骨细胞代谢中起着关键作用，但参与软骨稳态和骨关节炎（osteoarthritis，OA）发生发展的TGFβ信号通路和靶基因仍不清楚。我们采用体外细胞培养方法和体内小鼠遗传学方法，进行了这项研究，以研究软骨细胞中的TGFβ信号转导，并确定Mmp 13和Adamts 5是否是TGFβ信号转导的关键下游靶基因。通过将TGFβRIIflox/flox小鼠与Col 2-CreER转基因小鼠交配产生TGFβRII条件性敲除（KO）（TGFβ RIICol 2 ER）小鼠。进行组织学、组织形态学和基因表达分析。使用软骨形成大鼠软骨肉瘤细胞进行体外TGFβ信号转导研究。为了确定Mmp 13和ADAMTS 5是否是TGFβ信号传导的关键下游靶基因，产生并分析TGFβRII/基质金属蛋白酶13（MMP-13）-和TGFβRII/ADAMTS-5-双KO小鼠。抑制TGFβ信号传导（软骨细胞中Tgfbr 2基因的缺失）导致关节软骨组织中Runx 2、Mmp 13和Adamts 5表达上调，并导致TGFβ RIICol 2 ER小鼠中OA进展。Mmp 13或Adamts 5基因的缺失显著改善了由TGFβ信号转导的缺失诱导的OA样表型。用MMP-13抑制剂治疗TGFβ RIICol 2 ER小鼠也减缓了OA进展。Mmp 13和Adamts 5是OA发生发展过程中TGFβ信号通路的关键下游靶基因。
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. 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 chondro-genic 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. 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. Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA.
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影响因子：
1.5
作者：
Chytil, A;Magnuson, MA;Moses, HL
通讯作者：
Moses, HL
影响因子：
27.4
作者：
Davidson, E. N. Blaney;Vitters, E. L.;van den Berg, W. B.
通讯作者：
van den Berg, W. B.
影响因子：
--
作者：
Majumdar, Manas K.;Askew, Roger;Glasson, Sonya S.
通讯作者：
Glasson, Sonya S.
DOI：
10.1083/jcb.139.2.541
发表时间：
1997-10-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Serra R;Johnson M;Filvaroff EH;LaBorde J;Sheehan DM;Derynck R;Moses HL
通讯作者：
Moses HL
影响因子：
1.5
作者：
Chen, Mo;Lichtler, Alexander C.;Chen, Di
通讯作者：
Chen, Di