A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis: a comparison with neutralization of mouse TNFα

摘要: Background and purpose: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNF alpha) is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using novel inhibitor Org 48762-0, we investigated inhibition compared this to anti-mouse (m) TNF alpha antibody treatment murine collagen-induced (CIA). Experimental approach: Pharmacological profiles 48762-0 were characterized assays, cellular assays lipopolysaccharide (LPS)-induced inflammation mice. effects mTNF alpha-neutralization on established examined CIA. Key results: potently inhibited with high degree selectivity. In reduced LPS-induced release. Oral administration mice showed drug-like pharmacokinetic properties cytokine production. These pharmacological characteristics prompted comparison efficacy anti-mTNF equally development when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached only. Further, micro-computed tomographical histopathological confirmed protective joint damage. Conclusions implications: targeting provided good tissue our experiments, neutralization produced less prominent suppression Our data suggest selective potent inhibitors RA.