T cells regulate the expression of matrix metalloproteinase in human osteoblasts via a dual mitogen-activated protein kinase mechanism
Article first published online: 3 APR 2003
Copyright © 2003 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 48, Issue 4, pages 993–1001, April 2003
How to Cite
Rifas, L. and Arackal, S. (2003), T cells regulate the expression of matrix metalloproteinase in human osteoblasts via a dual mitogen-activated protein kinase mechanism. Arthritis & Rheumatism, 48: 993–1001. doi: 10.1002/art.10872
- Issue published online: 3 APR 2003
- Article first published online: 3 APR 2003
- Manuscript Accepted: 19 DEC 2002
- Manuscript Received: 18 JUN 2002
- NIH. Grant Numbers: AR-32087, AR-46370
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 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.
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.