Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis.
Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis.
复制标题
DOI：
10.1002/art.27537
复制
发表时间：
2010-08
影响因子：
--
通讯作者：
O'Keefe, Regis J.
中科院分区：
文献类型：
--
作者：
Li, Tian-Fang;Gao, Lin;Sheu, Tzong-Jen;Sampson, Erik R.;Flick, Lisa M.;Konttinen, Yrjo T.;Chen, Di;Schwarz, Edward M.;Zuscik, Michael J.;Jonason, Jennifer H.;O'Keefe, Regis J.
探讨Smad 3在骨关节炎（OA）发生发展过程中的生物学意义、Smad 3与ATF-2在TGF-β信号通路中的相互作用以及ATF-2过表达和p38激活对软骨细胞分化的影响。通过显微CT和组织学检查Smad 3敲除（Smad 3 −/−）小鼠的关节疾病。许多体外方法，包括免疫染色，实时PCR，Western印迹，ATF-2 DNA结合试验和p38激酶活性试验，用于研究Smad 3 −/−小鼠中软骨细胞表型改变的各种信号应答和蛋白质相互作用。Smad 3 −/−小鼠逐渐形成终末期OA表型。TGF-β诱导的TAK 1-ATF-2信号在Smad 3 −/−软骨细胞中在p38 MAP激酶激活水平被破坏，导致ATF-2磷酸化和转录活性降低。将Smad 3重新引入Smad 3 −/−细胞恢复了正常的p38对TGF-β的反应。磷酸化p38通过与Smad 3 MH 1-连接结构域结合而与Smad 3形成复合物。此外，Smad 3抑制MAP激酶磷酸酶-1（MKP-1）对p38的去磷酸化作用。ATF-2过表达和p38激活均抑制野生型和Smad 3 −/−软骨细胞中X型胶原的表达。关节软骨和软骨膜中检测到p38;关节和胸骨软骨细胞表达p38亚型α、β和γ，但不表达δ。Smad 3参与OA的发生和发展。Smad 3的缺失消除了TAK 1-ATF-2信号传导，最有可能是通过破坏Smad 3-磷酸-p38复合物，从而促进P38去磷酸化和MKP-1的失活。p38和ATF-2激活抑制软骨细胞肥大。调节p38亚型的活性可能为OA提供一种新的治疗方法。
To investigate the biological significance of Smad3 in the progression of osteoarthritis (OA), the crosstalk between Smad3 and ATF-2 in the TGF-β signaling pathway, and the effects of ATF-2 overexpression and p38 activation in chondrocyte differentiation. Joint disease in Smad3 knockout (Smad3−/−) mice was examined by micro-CT and histology. Numerous in vitro methods including immunostaining, real-time PCR, Western blotting, an ATF-2 DNA-binding assay and a p38 kinase activity assay were used to study the various signaling responses and protein interactions underlying the altered chondrocyte phenotype in Smad3−/− mice. Smad3−/− mice gradually developed an end-stage OA phenotype. TGF-β-induced TAK1-ATF-2 signaling was disrupted in Smad3−/− chondrocytes at the level of p38 MAP kinase activation resulting in reduced ATF-2 phosphorylation and transcriptional activity. Re-introduction of Smad3 into the Smad3−/− cells restored the normal p38 response to TGF-β. Phospho-p38 formed a complex with Smad3 by binding to the Smad3 MH1-linker domains. Additionally, Smad3 inhibited the dephosphorylation of p38 by MAP kinase phosphatase-1 (MKP-1). Both ATF-2 overexpression and p38 activation repressed type X collagen expression in wild type and Smad3−/− chondrocytes. p38 was detected in articular cartilage and perichondrium; articular and sternal chondrocytes expressed p38 isoforms α, β and γ, but not δ. Smad3 is involved in both the onset and progression of OA. Loss of Smad3 abrogates TAK1-ATF-2 signaling, most likely by disrupting the Smad3-phospho-p38 complex and, thereby, promoting p38 dephosphorylation and inactivation by MKP-1. p38 and ATF-2 activation inhibit chondrocyte hypertrophy. Modulation of p38 isoform activity may provide a new therapeutic approach for OA.
登录
查看更多内容
DOI：
10.1073/pnas.0503617102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Kobayashi, T;Lyons, KM;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
4.8
作者：
Leivonen, SK;Chantry, A;Kähäri, VM
通讯作者：
Kähäri, VM
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J
影响因子：
3.7
作者：
Ionescu, AM;Schwarz, EM;O'Keefe, RJ
通讯作者：
O'Keefe, RJ
影响因子：
10.5
作者：
Breitwieser, Wolfgang;Lyons, Steve;Jones, Nic
通讯作者：
Jones, Nic