Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.
Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.
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DOI：
10.1186/ar2772
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发表时间：
2009
影响因子：
4.9
通讯作者：
Fearon U
中科院分区：
文献类型：
--
作者：
Moran EM;Mullan R;McCormick J;Connolly M;Sullivan O;Fitzgerald O;Bresnihan B;Veale DJ;Fearon U
本研究的目的是检测抗TNF-α治疗后患者中的IL-17 A以及IL-17 A对基质转换和软骨降解的影响。用ELISA和免疫组织化学方法检测类风湿关节炎（RA）关节中IL-17 A的表达。用IL-17 A +/- TNF-α和制瘤素M（OSM）刺激RA全滑膜组织外植体（RA ST）、原代滑膜成纤维细胞（RASFC）、人软骨和软骨细胞培养物。采用酶联免疫吸附试验（ELISA）和酶谱法检测基质金属蛋白酶（MMP）和组织抑制因子（TIMP-1）的表达。通过番红-O染色在组织学上评估胡萝卜素蛋白聚糖释放。在生物治疗前后评估患者的临床参数、IL-17 A、MMP/TIMP。RA组IL-17 A水平高于OA组（P < 0.05）。IL-17 A可上调RA ST、RASFC、软骨及软骨细胞培养中MMP-1、MMP-2、MMP-9和MMP-13的表达（P < 0.05）。IL-17 A与TNF-α、OSM联合应用可使MMP/TIMP-1比值发生变化，有利于基质降解（P均< 0.05）。IL-17 A引起的Carbohydrin蛋白聚糖耗竭轻微;然而，与TNF-α或OSM联合使用时，显示蛋白聚糖几乎完全耗竭。在28%开始生物治疗的患者中检测到血清IL-17 A。IL-17 A阴性患者治疗后血清MMP 1/TIMP 4、MMP 3/TIMP 1和MMP 3/TIMP 4比值降低，CS 846升高（均P < 0.05）。在IL-17 A阳性患者中未观察到显著变化。IL-17 A在发炎的RA关节中局部产生。IL-17 A促进基质周转和软骨破坏，特别是在其他细胞因子存在下，模拟关节环境。IL-17 A水平在抗TNF治疗后在体内被调节，并且可以反映基质周转的变化。
The aim of this study was to examine IL-17A in patients, following anti-TNF-α therapy and the effect of IL-17A on matrix turnover and cartilage degradation. IL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +/- TNF-α and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP/TIMP were assessed in patients pre/post biologic therapy. IL-17A levels were higher in RA vs osteoarthritis (OA)/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-α and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-α or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1/TIMP4, MMP3/TIMP1 and MMP3/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients. IL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.
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影响因子：
--
作者：
Cho, ML;Yoon, CH;Kim, HY
通讯作者：
Kim, HY
影响因子：
2.2
作者：
Kohno, Mika;Tsutsumi, Akito;Sumida, Takayuki
通讯作者：
Sumida, Takayuki
影响因子：
3.8
作者：
Chabaud, M;Garnero, P;Miossec, P
通讯作者：
Miossec, P
影响因子：
--
作者：
Joosten, Leo A. B.;Abdollahi-Roodsaz, Shahla;van den Berg, Wirn B.
通讯作者：
van den Berg, Wirn B.
影响因子：
--
作者：
Joosten, LAB;Radstake, TRD;van den Berg, WB
通讯作者：
van den Berg, WB