Evaluation of the role of second messenger systems in tumor necrosis factor-stimulated resorption of fetal rat limb bones

G. Shankar, Paula H Stern*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Tumor necrosis factor (TNF) actions in target tissues are mediated by various signalling pathways. The effect of TNF to stimulate resorption in fetal rat limb bones is not inhibited by indomethacin. The current studies were designed to assess the role of cyclic AMP (cAMP) and calcium as second messengers in this prostaglandin-independent action of TNF on bone resorption. TNF alone failed to increase cyclic AMP in fetal rat limb bones after either brief (15 min) or long-term (72 h) treatment. TNF-stimulated resorption in fetal rat limb bones was enhanced by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). In short term incubations, the combination of TNF + IBMX did not elicit increases in cAMP in the limb bones. In 72 h cultures, addition of IBMX revealed a dose-dependent effect of TNF to increase cAMP. TNF produced a significant increase in inositol phosphate turnover in limb bones, with a greater response at 5 min than at 1 or 20 min. The calcium channel blocker nitrendipine inhibited TNF-stimulated resorption in the fetal rat limb bones. TNF-stimulated resorption was attenuated by pretreatment with pertussis toxin (PTx). PTx did not inhibit the effect of TNF to increase inositol phosphate turnover. TNF did not increase cAMP, intracellular calcium, or inositol phosphates in the UMR-106 cells. The data suggest the following: (a) cyclic mucleotides may play a role in TNF-stimulated resorption, although an increase in cAMP is not a direct rapid effect of TNF per se; (b) inositol phosphates could also play a signalling role in the action of TNF; (c) a pertussis toxin-sensitive step is required for TNF action on bone resorption.

Original languageEnglish (US)
Pages (from-to)871-876
Number of pages6
JournalBone
Volume14
Issue number6
DOIs
StatePublished - Jan 1 1993

Keywords

  • Bone resorption
  • Cyclic AMP
  • Inositol phosphates
  • Pertussis toxin
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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