ANTIINFLAMMATORY AND JOINT PROTECTIVE EFFECT OF SMP-114 IN MURINE COLLAGEN-INDUCED ARTHRITIS

Background: SMP-114, a novel isoxazole derivative, has been characterized as a compound with antiinflammatory activity in adjuvant arthritis rats and without any cyclooxygenase inhibitory activity. Collagen-induced arthritis has been widely used as an experimental model for rheumatoid arthritis to test antirheumatic agents.Objectives: To investigate the effects of SMP-114 on inflammation and bone destruction in murine collagen-induced arthritis, and on the in vitro osteoclast formation.Methods: The collagen-induced arthritis was performed in DBA/1J mice immunized on day 0 and 21 with bovine type II collagen. Animals were dosed with SMP-114 at 5, 10, 20, 40, or 80 mg/kg p.o., once daily for 35 consecutive days, beginning at the time of priming with collagen. Efficacy was assessed clinically, histologically and radiographically. Immune responses to type II collagen and serum levels of the acute-phase reactant, serum amyloid P component, were also evaluated. Cells from arthritic paws were cultured in vitro with or without SMP-114 for 7 days, and then stained for tartrate resistant acid phosphatase (TRAP), a marker of osteoclasts.Results: Mice that received SMP-114 at doses of 20 mg/kg or more developed arthritis at a lower frequency than the vehicle-treated controls. In the groups treated with SMP-114, the severity index of arthritis underwent only slight changes. SMP-114-treatment at doses of 5 mg/kg or higher resulted in marked suppression of the final severity index. Histologic analysis revealed that SMP-114 at doses of 10 mg/kg or more significantly reduced joint pathology, as determined by infiltration of inflammatory cells, pannus formation, and cartilage and bone damage. All mice treated with vehicle had radiographic evidence of joint destruction, characterized by joint space narrowing, bone erosions, and periarticular bony formation. The limbs of mice treated with SMP-114 exhibited much less severe changes than those of controls. Elevated serum anti-type II collagen antibodies and serum amyloid P component in collagen-induced arthritis mice were reduced dramatically by SMP-114. In vitro study showed that inflammatory cells of arthritic paws formed osteoclast-like cells spontaneously. SMP-114 reduced osteoclast formation.Conclusion: Symptoms of collagen-induced arthritis in mice are significantly reduced by treatment with SMP-114. Of particular note, this compound appears to exert a protective effect on joint damage. Suppression of osteoclast formation may contribute to the role of SMP-114 in anti-arthritic effect.Citation: , volume , supplement , year 2002, page Session: Rheumatoid arthritis – Treatment 2