Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments.
Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments.
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DOI：
10.1002/art.37922
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发表时间：
2013-06
影响因子：
--
通讯作者：
Loeser, Richard F.
中科院分区：
文献类型：
--
作者：
Long, David L.;Willey, Jeffrey S.;Loeser, Richard F.
基质片段，包括纤维连接蛋白片段(FNF)，在骨关节炎(OA)的发展过程中积累，刺激软骨细胞基质金属蛋白酶(MMP)的产生。本研究的目的是确定小GTPase rac1在FNF刺激的软骨细胞信号转导中的作用，从而导致基质金属蛋白酶-13的产生。正常人软骨取自组织供体，骨关节炎软骨取自膝关节置换标本。用化学抑制剂siRNA敲除、成分活性(CA)-RAC或显性负性(DN)-RAC腺病毒调节rac1的活性。无论是否加入已知的Rac激活剂、表皮生长因子或转化生长因子α(转化生长因子α)处理细胞。采用比色活性酶联免疫吸附试验、下拉试验和抗活性RAC的单抗免疫染色等方法检测细胞中的rac1活性。Rac1的化学抑制、siRNA的敲除和dN-RAC的表达阻断了FNF刺激的MMP13的产生，而CA-RAC的表达则增加了MMP13的表达。对Rho相关蛋白的抑制作用不明显。表皮生长因子和转化生长因子α可增加RAC1活性，促进基质金属蛋白酶-13的增加。免疫组织化学方法检测骨关节炎软骨中活性RAC的表达。Rac1是FNF诱导的信号转导所必需的，从而导致基质金属蛋白酶-13的产生增加。激活RAC的EGF受体配体可以促进这一效应。活性RAC在骨关节炎软骨中的存在和刺激基质金属蛋白酶-13产生的能力表明，它可能在骨关节炎的软骨基质破坏中发挥作用。
Matrix fragments, including fibronectin fragments (Fnf), accumulate during the development of osteoarthritis (OA) stimulating chondrocyte matrix metalloproteinase (MMP) production. The objective of this study was to determine the role of the small GTPase Rac1 in chondrocyte signaling stimulated by Fnf that results in MMP-13 production. Normal human cartilage was from tissue donors and OA cartilage from knee arthroplasty specimens. Rac1 activity was modulated with a chemical inhibitor, siRNA knock-down, constitutively active (CA)-Rac or dominant negative (DN)-Rac adenovirus. Cells were treated with Fnf or without known Rac activators, epidermal growth factor (EGF) or transforming growth factorα (TGFα). Rac1 activity was measured with a colorometric activity ELISA, pulldown assay, and immunostaining with a monoclonal antibody against active Rac. Chemical inhibition of Rac1, as well as knockdown by siRNA and expression of DN-Rac blocked Fnf stimulated MMP-13 production while expression of CA-Rac increased MMP-13. Inhibition of Rho-associated kinase had no effect. EGF and TGFα, but not Fnf, increased Rac1 activity and promoted the increase in MMP-13 above that stimulated by Fnf alone. Active Rac was detected by immunostaining in OA cartilage. Rac1 is required for Fnf induced signaling that results in increased MMP-13 production. EGF receptor ligands, which activate Rac, can promote this effect. The presence of active Rac in OA cartilage and the ability of Rac to stimulate MMP-13 production suggests that it could play a role in the cartilage matrix destruction seen in OA.
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DOI：
10.1084/jem.20062525
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Morita K;Miyamoto T;Fujita N;Kubota Y;Ito K;Takubo K;Miyamoto K;Ninomiya K;Suzuki T;Iwasaki R;Yagi M;Takaishi H;Toyama Y;Suda T
通讯作者：
Suda T
整合素通过依赖Rho GTPases的机制来使线粒体功能进行信号转导。
影响因子：
7.8
作者：
Werner, Erica;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
6.2
作者：
Zhang, Xianrong;Siclari, Valerie A.;Lan, Shenghui;Zhu, Ji;Koyama, Eiki;Dupuis, Holly L.;Enomoto-Iwamoto, Motomi;Beier, Frank;Qin, Ling
通讯作者：
Qin, Ling
影响因子：
56.9
作者：
Kheradmand, F;Werner, E;Werb, Z
通讯作者：
Werb, Z
影响因子：
7
作者：
Homandberg, GA;Wen, C;Hui, F
通讯作者：
Hui, F