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


CONCLUSIONS
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.
Rifas
Leonard
L
Washington University School of Medicine, St. Louis, Missouri 63110, USA. lrifas@imgate.wustl.edu
Arackal
Sophia
S
D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology*; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism*
D017077:Culture Media, Conditioned; D016207:Cytokines; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011994:Recombinant Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one