Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α.
Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α.
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DOI：
10.1002/art.30333
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发表时间：
2011-07
影响因子：
--
通讯作者：
Liu-Bryan, Ru
中科院分区：
文献类型：
--
作者：
Terkeltaub, Robert;Yang, Bing;Lotz, Martin;Liu-Bryan, Ru
IL-1β和TNFα刺激软骨细胞基质分解代谢反应，从而损害OA中的软骨稳态。AMPK调节能量稳态和细胞代谢，也在多种组织中发挥抗炎作用。在此，我们检验了AMPK活性限制软骨细胞基质对IL-1β和TNFα分解代谢反应的假设。采用Western blotting和免疫组化法检测AMPK α亚基的表达，并通过AMPKα Thr 172磷酸化状态检测AMPKα活性。分别采用DMMB法、Griess反应和Western blotting法检测软骨组织和软骨细胞对IL-1β和TNFα的促分解反应，如GAG、NO、MMP-3和MMP-13的释放。正常人膝关节软骨细胞表达AMPKα1、α2、β1、β2和γ1亚基。AMPK活性在正常人中组成性存在，但在OA关节软骨细胞和软骨中以及用IL-1β和TNFα处理的正常软骨细胞中降低。AMPKα的敲低导致软骨细胞对IL-1β和TNFα的分解代谢反应增强。此外，AMPK激活剂抑制软骨/软骨细胞对IL-1β和TNFα的促分解代谢反应以及TNFα和CXCL 8（IL-8）诱导X型胶原表达的能力。在用IL-1β或TNFα处理后，OA软骨和软骨细胞中AMPK活性降低。AMPK激活剂减弱AMPKα的去磷酸化和软骨细胞中由这些细胞因子诱导的促分解反应。这些观察结果表明，AMPK活性的维持通过保护软骨基质免受炎症诱导的降解来支持软骨稳态。
IL-1β and TNFα stimulate chondrocyte matrix catabolic responses, thereby compromising cartilage homeostasis in OA. AMPK, which regulates energy homeostasis and cellular metabolism, also exerts anti-inflammatory effects in multiple tissues. Here, we tested the hypothesis that AMPK activity limits chondrocyte matrix catabolic responses to IL-1β and TNFα. Expression of AMPK subunits was examined, and AMPKα activity was ascertained by phosphorylation status of AMPKα Thr172 in human knee articular chondrocytes and cartilage by Western blotting and immunohistochemistry, respectively. Pro-catabolic responses to IL-1β and TNFα such as release of GAG, NO, MMP-3 and MMP-13 were determined by DMMB assay, Griess reaction and Western blotting, respectively, in cartilage explants and chondrocytes with and without knockdown of AMPKα by siRNA approach. Normal human knee articular chondrocytes express AMPKα1, α2, β1, β2 and γ1 subunits. AMPK activity is constitutively present in normal, but is decreased in OA articular chondrocytes and cartilage, and in normal chondrocytes treated with IL-1β and TNFα. Knockdown of AMPKα results in enhanced catabolic responses to IL-1β and TNFα in chondrocytes. Moreover, AMPK activators suppress cartilage/chondrocyte pro-catabolic responses to IL-1β and TNFα and the capacity of TNFα and CXCL8 (IL-8) to induce type X collagen expression. AMPK activity is reduced in OA cartilage and in chondrocytes following treatment with IL-1β or TNFα. AMPK activators attenuate dephosphorylation of AMPKα and pro-catabolic responses in chondrocytes induced by these cytokines. These observations suggest that maintenance of AMPK activity supports cartilage homeostasis by protecting cartilage matrix from inflammation-induced degradation.
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影响因子：
5.2
作者：
Greer EL;Banko MR;Brunet A
通讯作者：
Brunet A
影响因子：
3.5
作者：
Davies, SP;Helps, NR;Hardie, DG
通讯作者：
Hardie, DG
影响因子：
4.9
作者：
Grogan SP;Miyaki S;Asahara H;D'Lima DD;Lotz MK
通讯作者：
Lotz MK
影响因子：
5.5
作者：
Goldring, SR
通讯作者：
Goldring, SR
影响因子：
2.9
作者：
FARNDALE, RW;SAYERS, CA;BARRETT, AJ
通讯作者：
BARRETT, AJ