Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling.
Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling.
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DOI：
10.1136/annrheumdis-2014-205779
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发表时间：
2015-12
影响因子：
27.4
通讯作者：
Liu CJ
中科院分区：
文献类型：
--
作者：
Zhao YP;Liu B;Tian QY;Wei JL;Richbourgh B;Liu CJ
前颗粒蛋白（PGRN）以前被分离为骨关节炎（OA）相关的生长因子。此外，PGRN通过拮抗肿瘤坏死因子α (TNF-α)在炎性关节炎小鼠模型中发挥治疗作用。本研究旨在探讨PGRN在骨性关节炎软骨降解和进展中的作用。在野生型和pgrn缺陷小鼠自发和手术诱导的OA模型中分析OA的进展。采用红素O染色、免疫组织化学和ELISA法评价软骨降解和OA。此外，我们还分析了骨性关节炎中已知参与软骨退变的退行性因子和分解代谢标志物的mRNA表达。此外，PGRN的合成代谢作用和潜在的机制研究通过体外实验在原代软骨细胞。在这里，我们发现PGRN的缺乏导致“衰老”小鼠自发的oa样表型。此外，PGRN缺陷小鼠表现出严重的软骨结构破坏和OA进展，而在手术诱导的OA模型中，局部递送重组PGRN蛋白可减轻软骨基质的降解并防止OA的发生。此外，PGRN激活细胞外信号调节激酶（ERK） 1/2信号传导，提高人软骨细胞中合成代谢生物标志物的水平，PGRN的保护功能主要通过TNF受体2介导。此外，PGRN抑制TNF-α的炎症作用，抑制软骨和软骨细胞中β-Catenin信号的激活。总的来说，这项研究为OA的发病机制提供了新的见解，也表明PGRN是治疗包括OA在内的关节退行性疾病的潜在靶点。
Progranulin (PGRN) was previously isolated as an osteoarthritis (OA)-associated growth factor. Additionally, PGRN was found to play a therapeutic role in inflammatory arthritis mice models through antagonising tumour necrosis factor α (TNF-α). This study was aimed at investigating the role of PGRN in degradation of cartilage and progression of OA. Progression of OA was analysed in both spontaneous and surgically induced OA models in wild type and PGRN-deficient mice. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry and ELISA. Additionally, mRNA expression of degenerative factors and catabolic markers known to be involved in cartilage degeneration in OA were analysed. Furthermore, the anabolic effects and underlying mechanisms of PGRN were investigated by in vitro experiments with primary chondrocytes. Here, we found that deficiency of PGRN led to spontaneous OA-like phenotype in `aged' mice. Additionally, PGRN-deficient mice exhibited exaggerated breakdown of cartilage structure and OA progression, while local delivery of recombinant PGRN protein attenuated degradation of cartilage matrix and protected against OA development in surgically induced OA models. Furthermore, PGRN activated extracellular signal-regulated kinases (ERK) 1/2 signalling and elevated the levels of anabolic biomarkers in human chondrocyte, and the protective function of PGRN was mediated mainly through TNF receptor 2. Additionally, PGRN suppressed inflammatory action of TNF-α and inhibited the activation of β-Catenin signalling in cartilage and chondrocytes. Collectively, this study provides new insight into the pathogenesis of OA, and also presents PGRN as a potential target for the treatment of joint degenerative diseases, including OA.
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影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
82.9
作者：
He, ZH;Ong, CHP;Bateman, A
通讯作者：
Bateman, A
影响因子：
7
作者：
Lai, Y.;Yu, X-P.;Zhang, Y.;Tian, Q.;Song, H.;Mucignat, M. T.;Perris, R.;Samuels, J.;Krasnokutsky, S.;Attur, M.;Greenberg, J. D.;Abramson, S. B.;Di Cesare, P. E.;Liu, C. J.
通讯作者：
Liu, C. J.
影响因子：
15.9
作者：
Kessenbrock, Kai;Froehlich, Leopold;Jenne, Dieter E.
通讯作者：
Jenne, Dieter E.