p38gamma mitogen-activated protein kinase suppresses chondrocyte production of MMP-13 in response to catabolic stimulation.
p38gamma mitogen-activated protein kinase suppresses chondrocyte production of MMP-13 in response to catabolic stimulation.
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DOI：
10.1016/j.joca.2010.05.016
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发表时间：
2010-09
影响因子：
7
通讯作者：
Loeser RF
中科院分区：
文献类型：
--
作者：
Long DL;Loeser RF
信号蛋白 p38 丝裂原激活蛋白激酶是软骨细胞中调节 MMP 产生的炎症信号所必需的。我们试图确定特定 p38 亚型在响应 IL-1β 和纤连蛋白片段的软骨细胞分解代谢信号传导中的作用。从组织供体的正常踝关节软骨或膝关节置换过程中获得的骨关节炎膝软骨中分离出的人关节软骨细胞，用 IL-1β 或纤连蛋白片段 (Fn-f) 进行刺激，并用或不用 p38 抑制剂（SB203580 或 BIRB796）或生长因子（IGF-1 和 OP-1）进行预处理。通过抗体阵列和免疫印迹测量p38亚型磷酸化。通过实时 PCR、ELISA 和免疫印迹测量 MMP-13 表达。用表达组成型活性（CA）p38γ的质粒或用表达显性失活（DN）p38γ的腺病毒转染软骨细胞。用 IL-1β 或 Fn-f 刺激软骨细胞导致 p38α 和 p38γ 磷酸化增强，而 p38β 或 p38δ 亚型磷酸化很少。 p38α 定位于细胞核，p38γ 定位于细胞质。与仅用 SB203580 抑制 p38α 相比，用 BIRB796 抑制 p38α 和 p38γ 导致对 IL-1β 或 FN-f 响应的 MMP-13 产生的抑制较小。 CAp38γ转染导致MMP-13产量减少，而DNp38γ转导导致MMP-13产量增加。 IGF-1 和 OP-1 预处理抑制 p38α 磷酸化，但不抑制 p38γ 磷酸化。 p38γ 通过人关节软骨细胞的分解代谢刺激而被激活，但有趣的是抑制 MMP-13 的产生。增加 p38γ 激活的治疗可能对减少软骨细胞 MMP-13 的产生具有治疗作用。
The signaling protein p38 mitogen-activated protein kinase is required for inflammatory signaling in chondrocytes that regulates MMP production. We sought to determine the role of specific p38 isoforms in chondrocyte catabolic signaling in response to IL-1β and fibronectin fragments. Human articular chondrocytes isolated from normal ankle cartilage from tissue donors or from osteoarthritic knee cartilage obtained during knee replacement were stimulated with IL-1β or fibronectin fragment (Fn-f), with or without pretreatment with p38 inhibitors (SB203580 or BIRB796) or growth factors (IGF-1 and OP-1). p38 isoform phosphorylation was measured by antibody array and immunoblotting. MMP-13 expression was measured by real-time PCR, ELISA, and immunoblotting. Chondrocytes were transfected with plasmids expressing constitutively active (CA) p38γ or with adenovirus expressing dominant negative (DN) p38γ. Stimulation of chondrocytes with either IL-1β or Fn-f led to enhanced phosphorylation of p38α and p38γ, with little phosphorylation of p38β or p38δ isoforms. p38α localized to the nucleus and p38γ to the cytosol. Inhibition of both p38α and p38γ with BIRB796 resulted in less inhibition of MMP-13 production in response to IL-1β or FN-f than did inhibition of only p38α with SB203580. Transfection with CAp38γ resulted in decreased MMP-13 production while transduction with DNp38γ resulted in increased MMP-13 production. IGF-1 and OP-1 pretreatment inhibited p38α phosphorylation but not p38γ phosphorylation. p38γ is activated by catabolic stimulation of human articular chondrocytes, but interestingly suppresses MMP-13 production. Treatments that increase p38γ activation may be of therapeutic benefit in reducing chondrocyte production of MMP-13.
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