Inhibition of the IL-1β-induced Expression of Matrix Metalloproteinases by Controlled Release of IL-1 Receptor Antagonist Using Injectable and Thermo-reversible Gels in Human Osteoarthritis Chondrocytes

Abstract

Objective. IL-1β is involved in the degradation of articular cartilage in various arthritides, including osteoarthritis (OA). Competitive inhibition of IL-1β by IL-1 receptor antagonists (IL-1Ra) may represent a pathogenesis-based strategy for inhibiting degradation of the cartilage matrix. We investigated the hypothesis that controlled release of IL-1Ra using injectable, thermoreversible and complex coacervate combination gels as drug delivery systems might reduce matrix degradation in OA. Methods. Thermoreversible combination gels that can be injected into joints were formed in aqueous solution by making a complex coacervate with recombinant human IL-1Ra (anakinra) and cationic macromolecules, and this was followed by co-formulation with methylcellulose as a negative thermosensitive polysaccharide. Gels containing anakinra were positioned in the upper insert of a transwell system and human OA chondrocytes were placed in the lower compartment and then they were stimulated with IL-1β. The expression of matrix metalloproteinases (MMPs) was examined by performing real time PCR and ELISA. Results. Complex coacervation between anakinra and protamine was successfully completed. IL-1Ra was released from the gels in a sustained release pattern for extended periods with minimal initial bursts. IL-1β markedly enhanced the expression of MMP. The IL-1Ra released from the gels significantly inhibited the IL-1β-induced MMP expression in the chondrocytes. Conclusion. We developed and optimized a novel injectable and thermoreversible gel system for the controlled release of IL-1Ra, and this drug delivery system effectively inhibited the IL-1β-induced MMP expression of chondrocytes in a transwell system. Intra-articular local delivery of injectable and thermoreversible gels containing IL-1Ra into knees has the potential to provide prolonged therapy based on the pathophysiology of knee OA.