IL-1- and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase.

Abstract

We have previously shown that p38 mitogen-activated protein kinase (MAPK) inhibitors, which block the production and action of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), are effective in models of bone and cartilage degradation. To further investigate the role of p38 MAPK, we have studied its activation in osteoblasts and chondrocytes, following treatment with a panel of proinflammatory and osteotropic agents. In osteoblasts, significant activation of p38 MAPK was observed following treatment with IL-1 and TNF, but not parathyroid hormone, transforming growth factor-beta (TGF-beta), 1,25(OH)(2)D(3), insulin-like growth factor-1 (IGF-1), or IGF-II. Similar results were obtained using primary bovine chondrocytes and an SV40-immortalized human chondrocyte cell line, T/C28A4. SB 203580, a selective inhibitor of p38 MAPK, inhibited IL-1 and TNF-induced p38 MAPK activity and IL-6 production (IC(50)s 0.3--0.5 microM) in osteoblasts and chondrocytes. In addition, IL-1 and TNF also activated p38 MAPK in fetal rat long bones and p38 MAPK inhibitors inhibited IL-1- and TNF-stimulated bone resorption in vitro in a dose-dependent manner (IC(50)s 0.3--1 microM). These data support the contention that p38 MAPK plays a central role in regulating the production of, and responsiveness to, proinflammatory cytokines in bone and cartilage. Furthermore, the strong correlation between inhibition of kinase activity and IL-1 and TNF-stimulated biological responses indicates that selective inhibition of the p38 MAPK pathway may have therapeutic utility in joint diseases such as rheumatoid arthritis (RA).

• Authors: S Kumar, B J Votta, D J Rieman, A M Badger, M Gowen, J C Lee
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 187 Issue 3 Pg. 294-303 (Jun 2001) ISSN: 0021-9541 [Print] United States
• PMID: 11319753 (Publication Type: Journal Article)
• Copyright: Copyright 2001 Wiley-Liss, Inc.

Chemical References

• Calcium Radioisotopes
• Cytokines
• Enzyme Inhibitors
• Growth Substances
• Interleukin-1
• Interleukin-6
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Biological Assay
• Bone Resorption (enzymology)
• Calcium Radioisotopes (analysis, metabolism)
• Cattle
• Cells, Cultured
• Chondrocytes (cytology, drug effects, enzymology)
• Culture Techniques
• Cytokines (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Growth Substances (pharmacology)
• Humans
• Interleukin-1 (metabolism, pharmacology)
• Interleukin-6 (biosynthesis)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Osteoblasts (cytology, drug effects, enzymology)
• Radius (cytology, embryology, enzymology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)
• Ulna (cytology, embryology, enzymology)
• p38 Mitogen-Activated Protein Kinases