Effect of FR133605, a novel cytokine suppressive agent, on bone and cartilage destruction in adjuvant arthritic rats.

Abstract

We evaluated the effect of FR133605, a novel inhibitor of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), on bone and cartilage destruction in adjuvant arthritic rats and compared it to corticosteroid, nonsteroidal antiinflammatory drugs (NSAID), and disease modifying antirheumatic drugs (DMARD). The antiinflammatory responses were evaluated by measurement of hind paw swelling, body weight, femoral bone mineral density, and glycosaminoglycan content (GAG) in femoral condyles in adjuvant arthritic rats. FR133605 inhibited IL-1 and TNF-alpha production stimulated with lipopolysaccharide (LPS) in human monocytes. FR133605 also inhibited serum IL-1 and TNF-alpha concentrations in LPS treated mice. In contrast, among comparison antirheumatic drugs, only corticosteroid inhibited production at nontoxic concentrations. In adjuvant arthritis, FR133605 significantly inhibited paw swelling, bone and cartilage destruction, and increased body weight. On the other hand, indomethacin significantly inhibited paw swelling, but not bone and cartilage loss. Dexamethasone completely inhibited paw swelling and bone loss, but augmented cartilage breakdown. DMARD weakly restored the loss of GAG contents in articular cartilage. FR133605 improved bone loss and articular cartilage destruction in adjuvant arthritic rats and the inhibitory effect was closely correlated with the suppressive activity of IL-1 and TNF-alpha production.