Open AccessProtective effect of RC‐3095, an antagonist of the gastrin‐releasing peptide receptor, in experimental arthritis
Author(s) -
Oliveira P. G.,
Grespan R.,
Pinto L. G.,
Meurer L.,
Brenol J. C. T.,
Roesler R.,
Schwartsmann G.,
Cunha F. Q.,
Xavier R. M.
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30486
Subject(s) - arthritis , proinflammatory cytokine , medicine , endocrinology , tumor necrosis factor alpha , gastrin releasing peptide , immunology , inflammation , receptor , neuropeptide , bombesin
Abstract Objective To evaluate the antiinflammatory effects of RC‐3095 in 2 experimental models of arthritis, collagen‐induced arthritis (CIA) and antigen‐induced arthritis (AIA), and to determine the mechanisms of action involved. Methods RC‐3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin‐releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin‐17 (IL‐17), IL‐1β, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme‐linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. Results In mice with AIA, administration of RC‐3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC‐3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC‐3095. Furthermore, arthritic mice treated with RC‐3095 showed a significant reduction in the concentrations of IL‐17, IL‐1β, and TNFα, and showed a diminished expression of GRPR. Conclusion These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.