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


METHODS
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.


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
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.
Mihara
K
K
Department of Pharmacology, NV Organon, Oss, The Netherlands. katsuhiro.mihara@organon.com
Almansa
C
C
Smeets
R L
RL
Loomans
E E M G
EE
Dulos
J
J
Vink
P M F
PM
Rooseboom
M
M
Kreutzer
H
H
Cavalcanti
F
F
Boots
A M
AM
Nelissen
R L
RL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D015153:Blotting, Western; D002356:Cartilage / Q000473:pathology; D019446:Endotoxemia / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011239:Prednisolone / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology*; D013379:Substrate Specificity; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D019138:Antibodies, Blocking; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C530087:Org 48762-0; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone; D048051:p38 Mitogen-Activated Protein Kinases