Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis.
Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis.
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DOI：
10.1002/art.38576
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发表时间：
2014-07
影响因子：
13.3
通讯作者：
Wei, Lei
中科院分区：
文献类型：
--
作者：
Wang, Shaowei;Wei, Xiaochun;Zhou, Jingming;Zhang, Jing;Li, Kai;Chen, Qian;Terek, Richard;Fleming, Braden C.;Goldring, Mary B.;Ehrlich, Michael G.;Zhang, Ge;Wei, Lei
确定关节内补充α-2巨球蛋白（A2 M）是否在大鼠OA模型中具有软骨保护作用。通过Western印迹、质谱、ELISA和免疫组织化学（IHC）比较来自正常和骨关节炎（OA）患者的血清、滑液（SF）和软骨中的A2 M浓度，A2 M被鉴定为潜在的治疗剂。用Luminex和ELISA法检测A2 M对IL-1诱导的软骨分解代谢酶的影响。在随机分配至四种处理的雄性大鼠（N=120）中评价对软骨变性和MMP-13浓度的体内作用：（1）CLT+盐水，（2）ACLT+ A2 M（lIU/kg），（3）ACLT+ A2 M（2 IU/kg）或（4）假手术+盐水。关节内注射6周。采用ELISA法测定SF灌洗液中MMP-13的浓度。通过RT-qPCR定量OA相关基因表达。进行组织学检查以分级OA。在正常人和OA患者中，SF中A2 M的水平低于血清，而MMP-13在SF中高于OA患者血清。在体外，A2 M抑制MMP-13的诱导IL-1在人软骨细胞中以剂量依赖性的方式。在大鼠ACLT OA模型中，补充关节内注射A2 M降低SF中MMP-13的浓度，对OA相关基因表达具有有利影响，并减弱OA进展。A2 M是一种血浆蛋白酶抑制剂，其浓度不足以抑制OA SF中发现的高浓度分解代谢因子。我们的研究结果表明，补充关节内A2 M提供了创伤后OA的软骨保护。
To determine if supplemental intra-articular alpha-2 macroglobulin (A2M) has a chondroprotective effect in a rat OA model. A2M was identified as a potential therapeutic agent by comparing A2M concentrations in serum, synovial fluid (SF), and cartilage from normal and osteoarthritic (OA) patients by Western blotting, mass spectrometry, ELISA, and immunohistochemistry (IHC). The effects of A2M on IL-1-induced cartilage catabolic enzymes were evaluated by Luminex and ELISA in cultured chondrocytes. In vivo effects on cartilage degeneration and MMP-13 concentration were evaluated in male rats (N=120) randomized to four treatments: (1) CLT+saline, (2) ACLT+A2M (1IU/kg), (3) ACLT+A2M (2IU/kg) or (4) sham surgery+saline. Intra-articular injections were given for 6 weeks. The concentration of MMP-13 in SF lavages was measured using ELISA. OA-related gene expression was quantified by RT-qPCR. Histology was performed to grade OA. In both normal and OA patients, the levels of A2M were lower in SF compared to serum, and MMP-13 was higher in SF than serum of OA patients. In vitro, A2M inhibited the induction of MMP-13 by IL-1 in a dose-dependent manner in human chondrocytes. In the rat ACLT OA model, supplemental intra-articular injection of A2M reduced the concentration of MMP-13 in SF, had a favorable effect on OA-related gene expression, and attenuated OA progression. A2M is a plasma protease inhibitor that is not present in sufficient concentrations to inactivate the high concentrations of catabolic factors found in OA SF. Our findings suggest that supplemental intra-articular A2M provides chondral protection for post traumatic OA.
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Jay, Gregory D.;Fleming, Braden C.;Watkins, Bryn A.;McHugh, Karen A.;Anderson, Scott C.;Zhang, Ling X.;Teeple, Erin;Waller, Kimberly A.;Elsaid, Khaled A.
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通讯作者：
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