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

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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 α (TNFα), transforming growth factor β (TGFβ), interferon‐γ (IFNγ), and interleukin‐17 (IL‐17) for their roles in MMP‐13 induction. Although individual cytokines had no significant effect, the combination of TNFα, TGFβ, IFNγ, 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.

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