title: Interactions of tumor necrosis factor with local and systemic factors in fetal rat limb bones.
abstract: In many tissues the actions of tumor necrosis factor-alpha (TNF) are indirectly mediated through the production of autacoids or other cytokines. To determine the role that these factors might have in the action of TNF on bone resorption, we examined the effects of several selective inhibitors on TNF-stimulated resorption. The cyclooxygenase inhibitor indomethacin did not prevent TNF-stimulated resorption in fetal rat limb bones. Stimulation of resorption by TNF was also unaffected by the platelet activating factor antagonist WEB 2086. A 17.5 kD interleukin receptor antagonist protein, at concentrations that completely blocked the bone-resorbing actions of maximally effective concentrations of interleukin (IL)-1 beta, failed to affect the stimulatory actions of TNF. TNF-stimulated resorption was inhibited by both interferon-gamma and dexamethasone. Dexamethasone inhibited TNF-stimulated resorption more effectively than it inhibited parathyroid hormone (PTH)-stimulated resorption. When bones were treated simultaneously with low concentrations of TNF and PTH, potentiation of the bone-resorbing effects was elicited. These results suggest that TNF stimulates resorption through a pathway different from that by which PTH produces its effects. Transforming growth factor-beta (TGF-beta) enhanced responses to TNF; TGF-beta failed to inhibit the effects of TNF, even in long-term culture or when bones were pretreated with TGF-beta. Synergistic interactions between TNF and several other bone-resorbing factors have now been demonstrated. In contrast to the actions of TNF on certain other functions, the bone-resorbing effects of TNF, as determined in the fetal rat limb bone system, do not seem to be mediated by PAF, IL-1, or prostaglandins.
authors.affiliation: Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611.
authors.forename: G
authors.initials: G
authors.lastname: Shankar
authors.forename: P H
authors.initials: PH
authors.lastname: Stern
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001862:Bone Resorption / Q000503:physiopathology*; D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology*; D046508:Culture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D006614:Hindlimb; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001381:Azepines; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010281:Parathyroid Hormone; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C052518:WEB 2086; D003907:Dexamethasone; D007371:Interferon-gamma; D007213:Indomethacin