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

J Cell Physiol. 2001 Jun;187(3):294-303. doi: 10.1002/jcp.1082.


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).

MeSH terms

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


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