Glatiramer acetate (GA), the immunomodulatory drug, inhibits inflammatory mediators and collagen degradation in osteoarthritis (OA) cartilage

Abstract

SummaryObjectiveGlatiramer 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.DesignPrimary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E2 (PGE2) 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.ResultsGA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100μg) 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).ConclusionsThese 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