Division of Rheumatology, Department of Medicine, NYU School of Medicine, NYU Hospital for Joint Diseases, New York, NY 10003, USA.
Osteoarthritis Cartilage. 2011 Sep;19(9):1158-64. doi: 10.1016/j.joca.2011.06.006. Epub 2011 Jun 26.
Glatiramer acetate (GA), the generic name for Copaxone, an immunomodulatory agent, has been shown to induce interleukin-1 receptor antagonist (IL-1Ra) production in macrophages. We therefore tested the effects of GA on the catabolic activities of osteoarthritis (OA) chondrocytes.
Primary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E(2) (PGE(2)) were estimated in the cell culture supernatants and in vitro MMP-13 activity was measured using fluorogenic substrate. TaqMan Real-Time quantitative polymerase chain reaction (RT-qPCR) was performed to estimate relative expression levels of genes.
GA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100 μg) inhibited: (1) spontaneous collagen degradation as assayed by CTX II enzyme-linked immunosorbent assay (ELISA) [mean CTX II (ng/g cartilage)] in control was 7.79 [95% confidence interval (CI) 2.57-13.02]-3.415 (95% CI 0.81-6.02) (P=0.0286); (2) spontaneous proMMP-13 secretion [mean MMP-13 (ng/g cartilage)] in control was 16.98 (95% CI 7.739-26.23)-6.973 (95% CI 1.632-12.31) (P=0.0286); (3) production of IL-1β-induced inflammatory mediators such as nitric oxide (NO) [mean NO (μM)] in IL-1 cultures was 11.47 (95% CI 7.10-15.83)-0.87 (95% CI 0.18-1.56) (P=0.0022); and (4) recombinant MMP-13 in vitro activity (15-25%; P=0.004).
These data suggest that GA effects may be due to upregulation of IL-1Ra as well as direct inhibition of MMP-13 activity. Based on these studies, we propose that GA has potential for disease modifying properties in OA and should be evaluated in vivo in animal studies.
作为一种免疫调节剂，醋酸格拉替雷（GA），又名复泰奥，已被证明可诱导巨噬细胞产生白细胞介素-1 受体拮抗剂（IL-1Ra）。因此，我们检测了 GA 对骨关节炎（OA）软骨细胞分解代谢活性的影响。
本研究采用原代人软骨细胞和 OA 软骨外植体。细胞培养上清液中测定白细胞介素-1Ra（IL-1Ra）、前基质金属蛋白酶-13（proMMP-13）和前列腺素 E2（PGE2）的浓度，并用荧光底物法测定体外 MMP-13 活性。采用 TaqMan 实时定量聚合酶链反应（RT-qPCR）测定基因的相对表达水平。
GA 处理显著增加了两种培养模型中可溶性 IL-1Ra 的转录和产生（P=0.001）。此外，GA（100μg）的加入抑制了：（1）CTX II 酶联免疫吸附试验（ELISA）测定的自发性胶原降解[对照中 CTX II（ng/g 软骨）]从 7.79[95%置信区间（CI）2.57-13.02]降至 3.415（95%CI 0.81-6.02）（P=0.0286）；（2）自发性 proMMP-13 分泌[对照中 MMP-13（ng/g 软骨）]从 16.98（95%CI 7.739-26.23）降至 6.973（95%CI 1.632-12.31）（P=0.0286）；（3）IL-1 诱导的炎症介质如一氧化氮（NO）的产生[IL-1 培养物中平均 NO（μM）]从 11.47（95%CI 7.10-15.83）降至 0.87（95%CI 0.18-1.56）（P=0.0022）；（4）体外重组 MMP-13 活性（15-25%；P=0.004）。
这些数据表明，GA 的作用可能是由于 IL-1Ra 的上调以及 MMP-13 活性的直接抑制。基于这些研究，我们提出 GA 具有治疗 OA 的疾病修饰特性，应在动物研究中进行体内评估。
