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

Br J Pharmacol. 2008 May;154(1):153-64. doi: 10.1038/bjp.2008.53. Epub 2008 Feb 25.


Background and purpose: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNFalpha) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFalpha antibody treatment in murine collagen-induced arthritis (CIA).

Experimental approach: Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFalpha-neutralization on established arthritis were examined in murine CIA.

Key results: Org 48762-0 potently inhibited p38alpha kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFalpha release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFalpha-neutralization in CIA. Org 48762-0 and anti-mTNFalpha antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage.

Conclusions and implications: Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFalpha produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Antibodies, Blocking / therapeutic use*
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / pathology
  • Blotting, Western
  • Cartilage / pathology
  • Endotoxemia / drug therapy
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Inflammation / chemically induced
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Prednisolone / therapeutic use
  • Pyridines / pharmacology*
  • Substrate Specificity
  • Tomography, X-Ray Computed
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*


  • Anti-Inflammatory Agents
  • Antibodies, Blocking
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Org 48762-0
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Prednisolone
  • p38 Mitogen-Activated Protein Kinases