TY - JOUR
T1 - Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction
AU - Mbalaviele, Gabriel
AU - Anderson, Gary
AU - Jones, Amy
AU - De Ciechi, Pamela
AU - Settle, Steve
AU - Mnich, Steve
AU - Thiede, Mark
AU - Abu-Amer, Yousef
AU - Portanova, Joseph
AU - Monahan, Joseph
PY - 2006/6
Y1 - 2006/6
N2 - 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 p38α, but not p38β, p38δ, and p38γ isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-κB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-α 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-α, interleukin-1β, and RANKL. Although c-Jun NH2-terminal kinase and NF-κB 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.
AB - 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 p38α, but not p38β, p38δ, and p38γ isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-κB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-α 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-α, interleukin-1β, and RANKL. Although c-Jun NH2-terminal kinase and NF-κB 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.
UR - http://www.scopus.com/inward/record.url?scp=33646808648&partnerID=8YFLogxK
U2 - 10.1124/jpet.105.100362
DO - 10.1124/jpet.105.100362
M3 - Article
C2 - 16501068
AN - SCOPUS:33646808648
SN - 0022-3565
VL - 317
SP - 1044
EP - 1053
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -