THR 0921 , a novel peroxisome proliferator-activated receptor gamma agonist , reduces the severity of collagen-induced arthritis

THR0921 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent anti-diabetic properties. Because of the proposed role of PPARγ in inflammation, we investigated the potential of orally active THR0921 to inhibit the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by the injection of bovine type II collagen in complete Freund's adjuvant on days 0 and 21. Mice were treated with THR0921 (50 mg/kg/day) starting on the day of the booster injection and throughout the remaining study period. Both clinical disease activity scores as well as histological scores of joint destruction were significantly reduced in mice treated with THR0921 compared to untreated mice. Proliferation of isolated spleen cells, as well as circulating levels of IgG antibody to type II collagen, was decreased by THR0921. Moreover, spleen cell production of IFN-γ, tumor necrosis factor (TNF)-α and IL-1β in response to exposure to lipopolysaccharide or type II collagen was reduced by in vivo treatment with THR0921. Steady state mRNA levels of TNF-α, IL-1β, monocyte chemotactic protein-1 and receptor activator of nuclear factor κB ligand (RANKL) in isolated joints were all decreased in mice treated with THR0921. Finally, THR0921 inhibited osteoclast differentiation of bone marrow-derived cells stimulated with macrophage colony-stimulating factor and RANKL. In conclusion, THR0921 attenuates collagen-induced arthritis in part by reducing the immune response. As such, PPARγ may be an important therapeutic target for rheumatoid arthritis. Introduction Rheumatoid arthritis (RA) is characterized by a chronic Th-1 associated inflammatory process resulting in systemic immunological abnormalities and progressive joint destruction. Although the precise etiology and underlying mechanisms of RA remain to be elucidated, several mediators, and thus potential therapeutic targets, have emerged. Proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IL-1β play a key role affecting the imbalance between Th1 and Th2 cells, as well as the activation of other cytokines, chemokines and proteinases [1-5]. In addition, recent evidence indicates that osteoclasts may participate in joint destruction in both animal models of RA and human disease [6,7]. Receptor activator of nuclear factor κB ligand (RANKL) has been reported to be a potent regulator of osteoclast differentiation and activation [8-11]. Recent biological therapies against TNF-α and IL-1β have demonstrated promising effects protecting against progressive joint destruction [12-15]. The clinical use of these therapies has been limited, however, due to several issues, including safety and cost of treatment. Peroxisome proliferator-activated receptor (PPAR)γ is a member of the ligand-activated transcription factors in the nuclear receptor superfamily and was initially characterized as a key regulator of adipocyte differentiation and lipid metabolism [16,17]. Recent studies have demonstrated that PPARγ agonists prove to have anti-inflammatory and immunomodulatory therapeutic effects [2]. Indeed, the natural PPARγ ligand 15deoxy-Delta (12,14)-prostaglandin J2 as well as synthetic PPARγ agonists such as rosiglitazone and troglitazone have