C/EBP homologous protein drives pro-catabolic responses in chondrocytes.
C/EBP homologous protein drives pro-catabolic responses in chondrocytes.
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DOI：
10.1186/ar4415
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发表时间：
2013
影响因子：
4.9
通讯作者：
Liu-Bryan R
中科院分区：
文献类型：
--
作者：
Husa M;Petursson F;Lotz M;Terkeltaub R;Liu-Bryan R
C/EBP同源蛋白（CHOP）的过量表达是内质网（ER）应激引起的未折叠蛋白反应（UPR）的特征之一。在这里，我们专注于CHOP在软骨细胞中的表达和功能。我们研究了人膝骨关节炎（OA）软骨，培养在藻酸盐和牛软骨细胞进行亚致死生物力学损伤，和人尸检供体的膝关节软骨细胞。我们进行siRNA敲除和转染。在人膝骨关节炎软骨原位和体外培养的生物力学损伤的软骨细胞中，UPR活化增加。在正常人软骨细胞中，CHOP“功能获得”使软骨细胞对IL-1β诱导的一氧化氮（NO）和基质金属蛋白酶（MMP）-3释放敏感，而本身不诱导这些反应。过量的CHOP表达，本身，诱导超氧化物的产生和细胞凋亡。相反，CHOP和UPR特异性介体X-box结合蛋白（XBP 1）的siRNA敲低抑制了IL-1β引起的NO释放>80%（P <0.0005），并减弱了MMP-3的释放，而UPR介体GRP 78对这些反应的影响很小。已知抗炎代谢“超级调节剂”AMP激酶（AMPK）限制血管肌肉细胞中的UPR活化。CHOP支持IL-1β抑制软骨细胞中AMPK活性的能力。我们还观察到AMPK活性的抑制促进了软骨细胞CHOP表达的增加。相反，5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）对AMPK的药理学激活减弱了软骨细胞对生物力学损伤的CHOP表达。生物力学损伤和IL-1信号刺激软骨细胞中的UPR活化。CHOP介导软骨细胞对IL-1β的分解代谢和凋亡反应，部分通过抑制AMPK活性来实现。相反，过度CHOP活性的发展受到软骨细胞中AMPK活性的限制。我们的研究结果表明，AICAR和其他AMPK激活剂的潜在软骨保护机制。这项工作与OA的翻译相关，因为几种激活AMPK的药物已经在临床上用于关节炎（例如，变构AMPK激活剂水杨酸钠和高剂量阿司匹林，以及甲氨蝶呤，其通过产生AICAR激活AMPK）。
Excess C/EBP homologous protein (CHOP) expression is one feature of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Here, we focused on CHOP expression and function in chondrocytes. We studied human knee osteoarthritis (OA) cartilage, bovine chondrocytes cultured in alginate and subjected to sub-lethal biomechanical injury, and knee chondrocytes of human autopsy donors. We performed siRNA knockdown and transfection. UPR activation was increased in human knee OA cartilage in situ, and in biomechanically injured cultured chondrocytes in vitro. In normal human chondrocytes, CHOP “gain of function” sensitized chondrocytes to IL-1β induced nitric oxide (NO) and matrix metalloproteinase (MMP)-3 release without inducing these responses by itself. Excess CHOP expression, by itself, induced superoxide production and apoptosis. Conversely, siRNA knockdown of CHOP and the UPR-specific mediator X-box binding protein (XBP1) inhibited NO release by >80% (P <0.0005) in response to IL-1β, and blunted MMP-3 release, whereas there were only minimal effects of the UPR mediator GRP78 on these responses. The anti-inflammatory metabolic “super-regulator” AMP kinase (AMPK) is known to limit UPR activation in vascular muscle cells. Here, CHOP supported the capacity of IL-1β to suppress AMPK activity in chondrocytes. We also observed that inhibition of AMPK activity promoted an increase in chondrocyte CHOP expression. Conversely, pharmacologic activation of AMPK by 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) blunted chondrocyte CHOP expression in response to biomechanical injury. Biomechanical injury and IL-1 signaling stimulate UPR activation in chondrocytes. CHOP mediates chondrocyte catabolic and apoptotic responses to IL-1β, and does so partly by inhibiting AMPK activity. Conversely, development of excess CHOP activity is limited by AMPK activity in chondrocytes. Our findings suggest a mechanism for potential chondroprotection by AICAR and other AMPK activators. The work is of translational relevance for OA, since several drugs that activate AMPK are already in the clinic for arthritis (for example, allosteric AMPK activators sodium salicylate and high dose aspirin, and methotrexate, which activates AMPK by generating AICAR).
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
DOI：
10.1126/science.1215327
发表时间：
2012-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hawley SA;Fullerton MD;Ross FA;Schertzer JD;Chevtzoff C;Walker KJ;Peggie MW;Zibrova D;Green KA;Mustard KJ;Kemp BE;Sakamoto K;Steinberg GR;Hardie DG
通讯作者：
Hardie DG
影响因子：
3.2
作者：
Nugent, Ashleigh E.;Speicher, Danielle M.;Horton, Walter E., Jr.
通讯作者：
Horton, Walter E., Jr.
影响因子：
4.8
作者：
Pereira, RC;Delany, AM;Canalis, E
通讯作者：
Canalis, E
影响因子：
5.6
作者：
Price, Jeremy;Zaidi, Asifa K.;Ali, Hydar
通讯作者：
Ali, Hydar