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Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction
Gabriel Mbalaviele1, Gary Anderson, Amy Jones
1Department of Inflammation, Pfizer Inc., 700 Chesterfield Parkway West, Mail Stop AA5G, Chesterfield, MO 63017, USA. gabriel.mbalaviele@pfizer.com
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.
Insights
A novel p38 inhibitor, SC-409, effectively blocked osteoclast development and reduced joint destruction in rheumatoid arthritis models. This suggests p38 MAPK inhibition is a promising therapeutic strategy for preventing bone loss in RA.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Mitogen-activated protein kinase (MAPK) pathways, particularly p38 MAPK, are involved in joint destruction in rheumatoid arthritis (RA).
- The precise mechanisms by which p38 MAPK contributes to osteolysis in arthritis are not fully understood.
- Osteoclast (Ocl) precursors express p38alpha, a key isoform in inflammatory signaling.
Purpose of the Study:
- To investigate the role of p38 MAPK in osteoclastogenesis and bone destruction in rheumatoid arthritis.
- To evaluate the efficacy of a novel p38 inhibitor, SC-409, in preclinical models of arthritis.
- To elucidate the downstream signaling pathways affected by p38 MAPK inhibition.
Main Methods:
- In vitro studies using osteoclast precursors treated with RANKL and TNF-alpha.
- In vivo studies using a rat model of streptococcal cell wall (SCW)-induced arthritis.
- Administration of the p38 inhibitor SC-409 to assess its effects on Ocl development, joint swelling, and bone destruction.
- Analysis of downstream signaling pathways including myocyte-enhancing factor 2 C, TNF-alpha, IL-1beta, RANKL, c-Jun NH2-terminal kinase, and NF-kappaB.
Main Results:
- SC-409 significantly inhibited RANKL-induced osteoclast development in vitro.
- SC-409 treatment attenuated joint swelling and bone destruction in the SCW-induced arthritis rat model.
- SC-409 inhibited SCW-induced activation of myocyte-enhancing factor 2 C and suppressed the expression of TNF-alpha, IL-1beta, and RANKL.
- SC-409 did not significantly affect the activation of c-Jun NH2-terminal kinase and NF-kappaB pathways.
Conclusions:
- p38 MAPK plays a critical role in modulating cytokine production and signaling, contributing to bone loss in arthritis.
- The novel p38 inhibitor SC-409 demonstrates potent bone-sparing effects in a rat arthritis model.
- Targeting p38 MAPK pathways represents a potential therapeutic strategy for preventing bone destruction in rheumatoid arthritis.
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