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

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).
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.
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.
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.
AuthorsLeonard Rifas, Sophia Arackal
JournalArthritis and rheumatism (Arthritis Rheum) Vol. 48 Issue 4 Pg. 993-1001 (Apr 2003) ISSN: 0004-3591 [Print] United States
PMID12687541 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Culture Media, Conditioned
  • Cytokines
  • Drug Combinations
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Pyridines
  • Recombinant Proteins
  • SB 203580
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • 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)

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