Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1beta through the NF-kappaB and MAPK pathways in rheumatoid arthritis.

Abstract

OBJECTIVE:

Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1beta (MIP-1beta), in RA.

METHODS:

Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation.

RESULTS:

The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP-1 and MIP-1beta in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP-1 or MIP-1beta in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP-1 or MIP-1beta, and this effect could be blocked by an anti-OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50-83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF-kappaB and MAPK pathways, involving the activation of IKKbeta, p38, and JNK.

CONCLUSION:

These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP-1 and MIP-1beta.

• Authors: Wenxin Zheng, Runsheng Li, Heng Pan, Dongyi He, Rong Xu, Taylor B Guo, Yajun Guo, Jingwu Z Zhang
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 7 Pg. 1957-65 (Jul 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19565503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL2 protein, human
• Chemokine CCL2
• Chemokine CCL4
• Lipopolysaccharide Receptors
• NF-kappa B
• Osteopontin
• I-kappa B Kinase
• IKBKB protein, human
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases

Topics

• Adult
• Aged
• Arthritis, Rheumatoid (metabolism, pathology)
• Case-Control Studies
• Cell Movement (physiology)
• Cells, Cultured
• Chemokine CCL2 (metabolism)
• Chemokine CCL4 (metabolism)
• Female
• Humans
• I-kappa B Kinase (metabolism)
• Leukocytes, Mononuclear (metabolism, pathology)
• Lipopolysaccharide Receptors (metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• NF-kappa B (metabolism)
• Osteopontin (metabolism)
• Signal Transduction (physiology)
• Synovial Fluid (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)