Injectable, thermo-reversible and complex coacervated combination gels containing IL-1 receptor antagonis inhibits IL-1 beta-induced MMP-3 expression in human osteoarthritis chondrocytes

Abstract

IL-1 has been implicated in degradation of articular cartilage in various arthritides including osteoarthritis (OA). Therefore, blocking of IL-1 by IL-1 receptor antagonist (IL-1Ra) may be the pathogenesis-based strategy for inhibiting degradation of cartilage matrix. We investigated the role of injectable, thermo-reversible and complex coacervated combination gels containing IL-1Ra for matrix degradation in OA.The combination gels, injectable to the joint, were formed in aqueous solution by preparing complex coacervate with IL-1Ra and cationic macromolecules, and co-formulating with methylcellulose. The gels containing IL-1Ra were positioned in upper insert of transwell system, and human OA chondrocytes were placed in lower compartment and stimulated with IL-1β. Expression of matrix metalloproteinase 3 (MMP-3) was examined by real time PCR and ELISA.Release profile of IL-1Ra from the gels showed a sustained release pattern through 6 days with minimal initial bursts. IL-1Ra-loaded gels after 5 days of formation were used. IL-1b markedly induced the expression of MMP-3 gene and protein. However, loading of combination gels containing IL-1Ra profoundly inhibited IL-1β-induced MMP-3 expression in human OA chondrocytes. We are planning to examine the effectiveness of 30 day-matured gels in degradation of extracellular matrix with articular chondrocytes and cartilage explants.We applied our optimized novel in situ gel depot system containing IL-1Ra to human OA chondrocytes in transwell system. According to our results, intraarticular injection of our gels containing IL-1Ra into OA knee will provide a prolonged therapeutic option based on the pathophysiology in the treatment of knee OA.