T cells regulate the expression of matrix metalloproteinase in human osteoblasts via a dual mitogen-activated protein kinase mechanism.

Abstract

OBJECTIVE:

To investigate the role of T cell induction of matrix metalloproteinase 13 (MMP-13) production by human osteoblasts in order to better understand the process of bone loss in rheumatoid arthritis (RA).

METHODS:

Activated T cell-conditioned medium (ACTTCM) was used to mimic the physiologic conditions of inflammation. MMP-13 production by human osteoblasts was assessed using a specific enzyme-linked immunosorbent assay. Specific inhibitors of the p38 mitogen-activated protein (MAP) kinase and the extracellular signal-regulated kinase 1/2 (ERK-1/2) MAP kinase signaling pathways were used to assess their roles in T cell-mediated MMP-13 production. Finally, recombinant cytokines representative of the major components in ACTTCM were assessed for their ability to induce MMP-13.

RESULTS:

ACTTCM powerfully induced MMP-13 in human osteoblasts. Inhibition of p38 activity abolished, while inhibition of ERK-1/2 activity enhanced, MMP-13 production. We next investigated physiologic levels of the T cell cytokines tumor necrosis factor alpha (TNFalpha), transforming growth factor beta (TGFbeta), interferon-gamma (IFNgamma), and interleukin-17 (IL-17) for their roles in MMP-13 induction. Although individual cytokines had no significant effect, the combination of TNFalpha, TGFbeta, IFNgamma, and IL-17 resulted in a dramatic p38-dependent induction of MMP-13 identical to that produced by ACTTCM.

CONCLUSION:

These studies demonstrate for the first time that human osteoblasts produce MMP-13. The results also show that under conditions of chronic inflammation, multiple T cell cytokines synergize to induce high levels of MMP-13 via a mechanism that is dependent on activated p38 MAP kinase and is suppressed by activated ERK-1/2. Selective inhibition of p38 activity may offer a target for pharmacologic inhibition of bone loss in RA.

• Authors: Leonard Rifas, Sophia Arackal
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 48 Issue 4 Pg. 993-1001 (Apr 2003) ISSN: 0004-3591 [Print] United States
• PMID: 12687541 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Culture Media, Conditioned
• Cytokines
• Drug Combinations
• Enzyme Inhibitors
• Flavonoids
• Imidazoles
• Pyridines
• Recombinant Proteins
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Collagenases
• MMP13 protein, human
• Matrix Metalloproteinase 13
• Mmp13 protein, mouse
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Cells, Cultured
• Collagenases (biosynthesis)
• Culture Media, Conditioned (pharmacology)
• Cytokines (metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Flavonoids (pharmacology)
• Humans
• Imidazoles (pharmacology)
• Matrix Metalloproteinase 13
• Mice
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Osteoblasts (drug effects, enzymology)
• Pyridines (pharmacology)
• Recombinant Proteins (pharmacology)
• T-Lymphocytes (metabolism)