ABSTRACT
Heme oxygenase-1 (HO-1), an inducible heme-degrading enzyme, is expressed by macrophages and endothelial cells in response to inflammatory stresses. It has been known to show strong immunosuppressive properties although its mechanisms are not completely understood. This study was designed to determine the effects of HO-1 modulation on collagen induced arthritis (CIA) model. CIA model was induced by subcutaneous injection of collagen on tail of DBA/1J mice. For evaluation of HO-1 effects, an inducer of HO-1, cobalt protoporphyrin IX (CoPPIX), or an inhibitor of HO-1, tin protoporphyrin IX (SnPPIX), were administered every other days into peritoneal cavity from day 1 to day 42 after CIA induction. The macrocopic clinical findings of CIA were evaluated and histo-pathologic findings and radiographic analysis were carried out. The expressions of TNF-alpha, IL-6, and VEGF which have important roles in pathogenesis of rheumatoid arthritis were observed by immuno-histochemical staining. Collagen on DBA/1J mice induced arthritis at knee joint and ankle joint. Administration of CoPPIX significantly aggravated the severity of arthritis while SnPPIX protected collagen induced arthritis. SnPPIX strongly suppressed inflammatory cell infiltration, swelling of synovial membrane, and erosion and destruction of bone on CIA mice. Furthermore subcutaneous injection of collagen also increased expression of TNF-alpha, IL-6, and VEGF which are important pro-inflammatory mediators in rheumatoid arthritis. SnPPIX suppressed expression of the pro-inflammatory mediators on CIA mice. Finally, we suggest that HO-1 mediates the expression of pro-inflammatory mediators and bone destruction during pathogenesis of CIA, which indicates modulation of HO-1 can be a new therapeutic target of rheumatoid arthritis.