Grant: Operating Grant

With a prevalence of ~0.6%, rheumatoid arthritis (RA) is the most common form of human inflammatory arthritis. In Canada alone, it is estimated that more than 100 000 people are diagnosed each year with this disorder, with a societal monetary cost measured in the billions. Since the pathogenic mechanisms of RA remain poorly understood, and current therapies are not preventive and remain only partially effective, further understanding of the pathogenic mechanisms and regulatory pathways active in synovial inflammation promises to yield more effective treatment for patients afflicted with this devastating illness. Among the different proteins detected in joints of patients with RA, the secreted phospholipase A2 (sPLA2) enzymes attracted considerable attention but the actual roles of these proteins in RA were never delineated. The sPLA2 family of enzymes, numbering 9 members in humans, is most studied for their role in generating substrate fatty acid for biosynthesis of lipid mediators. Given the recent insights into sPLA2 diversity, we reexamined sPLA2 expressions and contributions in inflammatory arthritis. Although several sPLA2 isoforms could be detected, our studies confirm the dominant expression of sPLA2-IIA in RA synovial fluids (SF). Importantly, we demonstrate a prominent proinflammatory activity for the sPLA2-IIA isoform in a murine model of arthritis. To our surprise, we also unveil an anti-inflammatory function for another sPLA2 isoform, sPLA2-V. This present research study will aim to unfold the mechanisms by which sPLA2-IIA contributes to arthritis and will examine the predicted necessity for highly selective therapeutic compounds targeting sPLA2-IIA -and not sPLA2-V- as a novel therapeutic for treatment of RA.