Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models.
Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models.
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DOI：
10.1186/s13075-017-1485-8
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发表时间：
2017-12-19
影响因子：
4.9
通讯作者：
Liu CJ
中科院分区：
文献类型：
--
作者：
Wei JL;Fu W;Ding YJ;Hettinghouse A;Lendhey M;Schwarzkopf R;Kennedy OD;Liu CJ
Atsttrin是一种由颗粒蛋白前体（PGRN）的三个肿瘤坏死因子受体（TNFR）结合片段组成的工程蛋白，在多种炎症性关节炎小鼠模型中显示出治疗效果。另外，PGRN的关节内递送防止骨关节炎（OA）进展。本研究的目的是确定Atsttrin是否对OA也有治疗作用及其分子机制。分别在小鼠和大鼠中建立手术诱导和非侵袭性破裂OA模型。采用番红O染色、免疫组化和ELISA评价了软骨素降解和OA。此外，疼痛相关标志物，退行性因子，以及已知参与OA的合成代谢和分解代谢标志物的表达进行了分析。此外，Atsttrin的合成代谢和抗分解代谢作用和潜在的机制使用原代软骨细胞的体外测定来确定。在此，我们发现Atsttrin有效地预防了与PGRN缺乏相关的加速OA表型。此外，Atsttrin在非手术诱导的大鼠和手术诱导的小鼠OA模型中通过保护关节软骨和减轻OA相关疼痛而表现出预防OA的作用。机制研究表明Atsttrin刺激TNFR 2-Akt-Erk 1/2依赖的软骨细胞凋亡，同时抑制TNFα/TNFR 1介导的炎性细胞增殖。这些发现不仅为PGRN及其衍生的工程蛋白Atsttrin在软骨稳态以及体内OA中的作用提供了新的见解，而且还可能为OA以及其他相关退行性关节疾病带来新的治疗选择。本文的在线版本（doi：10.1186/s13075-017-1485-8）包含补充材料，可供授权用户使用。
Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra-articular delivery of PGRN protects against osteoarthritis (OA) progression. The purpose of this study is to determine whether Atsttrin also has therapeutic effects in OA and the molecular mechanisms involved. Surgically induced and noninvasive rupture OA models were established in mouse and rat, respectively. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry, and ELISA. Additionally, expressions of pain-related markers, degenerative factors, and anabolic and catabolic markers known to be involved in OA were analyzed. Furthermore, the anabolic and anti-catabolic effects and underlying mechanisms of Atsttrin were determined using in-vitro assays with primary chondrocytes. Herein, we found Atsttrin effectively prevented the accelerated OA phenotype associated with PGRN deficiency. Additionally, Atsttrin exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erk1/2-dependent chondrocyte anabolism, while inhibiting TNFα/TNFR1-mediated inflammatory catabolism. These findings not only provide new insights into the role of PGRN and its derived engineered protein Atsttrin in cartilage homeostasis as well as OA in vivo, but may also lead to new therapeutic alternatives for OA as well as other relative degenerative joint diseases. The online version of this article (doi:10.1186/s13075-017-1485-8) contains supplementary material, which is available to authorized users.
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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：
6.1
作者：
Altmann, Christine;Hardt, Stefanie;Tegeder, Irmgard
通讯作者：
Tegeder, Irmgard
DOI：
10.1016/j.bbrc.2012.03.111
发表时间：
2012-05-11
影响因子：
3.1
作者：
Hattori, Yosuke;Kojima, Toshihisa;Ishiguro, Naoki
通讯作者：
Ishiguro, Naoki
促生蛋白：一种生长因子，一种新型的TNFR配体和药物靶标。
影响因子：
13.5
作者：
Liu, Chuan-ju;Bosch, Xavier
通讯作者：
Bosch, Xavier
影响因子：
3.5
作者：
Liu CJ
通讯作者：
Liu CJ