title: Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction.
abstract: Mitogen-activated protein kinase (MAPK) pathways are implicated in joint destruction in rheumatoid arthritis (RA) by modulating the production and functions of inflammatory cytokines. Although p38 MAPK (p38) participates in signaling cascades leading to osteolysis in arthritis, the mechanisms of its action in this process remain incompletely understood. Here, we found that the osteoclast (Ocl) precursors expressed p38alpha, but not p38beta, p38delta, and p38gamma isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-alpha was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409). To validate in vitro data, p38 role was further investigated in streptococcal cell wall (SCW)-induced arthritis in rats. We found that SCW-induced joint swelling and bone destruction were attenuated by SC-409. Mechanistically, the data show that SCW-stimulated DNA binding activity of the transcription factor myocyte-enhancing factor 2 C, which is downstream of p38, was inhibited by SC-409. In addition, SC-409 inhibited SCW-stimulated expression of numerous factors, including TNF-alpha, interleukin-1beta, and RANKL. Although c-Jun NH2-terminal kinase and NF-kappaB pathways were activated in vitro by RANKL and in vivo by SCW, SC-409 had no significant effect on these pathways. In conclusion, our data show that p38 modulates the production and signaling of cytokines, thus providing a mechanism of the bone-sparing effect of SC-409 in rat arthritis. These data present SC-409 as a novel potent p38 inhibitor and suggest that p38-based therapies may be beneficial in preventing bone loss associated with RA.
authors.affiliation: Department of Inflammation, Pfizer Inc., 700 Chesterfield Parkway West, Mail Stop AA5G, Chesterfield, MO 63017, USA. gabriel.mbalaviele@pfizer.com
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
authors.forename: Gary
authors.initials: G
authors.lastname: Anderson
authors.forename: Amy
authors.initials: A
authors.lastname: Jones
authors.forename: Pamela
authors.initials: P
authors.lastname: De Ciechi
authors.forename: Steve
authors.initials: S
authors.lastname: Settle
authors.forename: Steve
authors.initials: S
authors.lastname: Mnich
authors.forename: Mark
authors.initials: M
authors.lastname: Thiede
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
authors.forename: Joseph
authors.initials: J
authors.lastname: Portanova
authors.forename: Joseph
authors.initials: J
authors.lastname: Monahan
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D050281:Bones of Lower Extremity / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D053245:RANK Ligand; D051381:Rats; D011917:Rats, Inbred Lew; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases