Roles of Sphingosine-1 Phosaphate During Pathogenesis of Bone Destruction and Inflammation in Rheumatoid Arthritis Mice Model / 대한해부학회지

Sphingosine 1-phosphate (S1P) is a bioactive lipid molecule that mediates cell proliferation, differentiation, migration, and angiogenesis in vivo. However, the roles of S1P on pathogenesis of arthritis have been not completely understood. This study was designed to determine the effects of S1P modulation on collageninduced arthritis (CIA) model. DBA/1J mice were injected with collagen into the tail for induction of CIA model. S1P was administered into the peritoneal cavity every other days from day 1 to day 42 after collagen injection. To determine the degree of damage in CIA, we examined macroscopic findings of CIA. The inflammation and bone destruction of CIA mice were evaluated by histo-patholigy and radiography (CT and microradiography). The expressions of TNF-alpha, IL-6, and RANKL which have important roles in pathogenesis of rheumatoid arthritis and bone destruction were observed by immuno-histochemical staining. After injection with collagen in the DBA/1J mice, CIA was induced by swelling in the knee and ankle joint. Administration of S1P suppressed damages and incidence of arthritis elicited by collagen. In histologic and radiographic studies, S1P strongly suppressed the infiltration of inflammatory cells, the swelling of synovial membrane, erosion, and the destruction of bone on CIA mice. Injection of S1P resulted in down-regulation of the expression of the pro-inflammatory and bone destruction mediators such as TNF-alpha, IL-6, and RANKL on CIA mice. Furthermore, S1P suppressed the differentiation of bone marrow cells into osteoclasts by RANKL. In conclusion, this study suggest that S1P has protective effects on inflammation and bone destruction during pathogenesis of CIA, which indicates S1P can be a new possible therapeutic strategy for rheumatoid arthritis

The Effects of Heme Oxygenase-1 on Collagen Induced Arthritis Model / 대한해부학회지

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.