Research Paper
Subject Category: Immunopharmacology and inflammation
British Journal of Pharmacology (2008) 154, 153–164; doi:10.1038/bjp.2008.53; published online 25 February 2008
A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis: a comparison with neutralization of mouse TNF
K Mihara1, C Almansa2, R L Smeets1, E E M G Loomans3, J Dulos1, P M F Vink1, M Rooseboom1, H Kreutzer1, F Cavalcanti4, A M Boots1 and R L Nelissen1
- 1Department of Pharmacology, NV Organon, Oss, The Netherlands
- 2Department of Medicinal Chemistry, Palau Pharma SA, Barcelona, Spain
- 3Department of Molecular Pharmacology, NV Organon, Oss, The Netherlands
- 4Department of Discovery Biology, Palau Pharma SA, Barcelona, Spain
Correspondence: K Mihara, Department of Pharmacology, NV Organon, PO Box 20, Oss 5340 BH, The Netherlands. E-mail: katsuhiro.mihara@organon.com
Received 12 November 2007; Revised 17 January 2008; Accepted 31 January 2008; Published online 25 February 2008.
Abstract
Background and purpose:
The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-
(TNF) 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)TNF 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 mTNF-neutralization on established arthritis were examined in murine CIA.
Key results:
Org 48762-0 potently inhibited p38 kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNF 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 mTNF-neutralization in CIA. Org 48762-0 and anti-mTNF 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 mTNF produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.
Keywords:
p38 MAPK, Org 48762-0, anti-TNF therapy, collagen-induced arthritis, inflammation, rheumatoid arthritis, proinflammatory cytokines, bone damage
Abbreviations:
CIA, collagen-induced arthritis; IL, interleukin; IMAP, immobilized metal ion affinity-based fluorescence polarization; LPS, lipopolysaccharide; MK2, MAP kinase-activated protein kinase-2; RA, rheumatoid arthritis; TNF, tumour-necrosis factor
