Tumor necrosis factors alpha and beta can stimulate bone resorption in cultured mouse calvariae by a prostaglandin-independent mechanism.
Human recombinant tumor necrosis factors alpha and beta (TNF-alpha and TNF-beta), at and above 1 ng/ml (approximately equal to 70 pM), caused a dose- and time-dependent enhancement of 45Ca release from neonatal mouse calvarial bones in vitro. In addition, TNF-alpha and TNF-beta (3-100 ng/ml) caused a dose-dependent stimulation of prostaglandin E2 (PGE2) formation in the calvarial bones. TNF-alpha also enhanced the biosynthesis of PGI2, as assessed by analysis of the stable breakdown product 6-keto-PGF1 alpha. The stimulatory actions of TNF-alpha and TNF-beta on PGE2 formation was maximal at 12 h. Indomethacin, flurbiprofen, and meclofenamic acid, three structurally unrelated nonsteroidal antiinflammatory drugs, abolished PGE2 biosynthesis induced by TNF-alpha and TNF-beta (100 ng/ml). The 45Ca release stimulated by TNF-alpha and TNF-beta (100 ng/ml), however, was only slightly reduced by indomethacin, flurbiprofen, and meclofenamic acid. The partial inhibitory effect of indomethacin on 45Ca release was seen over a wide range of TNF-alpha concentrations, without affecting the concentration producing half-maximal stimulatory response. TNF-alpha and TNF-beta (100 ng/ml) stimulated bone matrix breakdown, as assessed by analysis of the release of 3H from bone prelabeled with [3H]proline. Also, the stimulatory effect of TNF-alpha and TNF-beta on bone matrix degradation was partially reduced by indomethacin. Hydrocortisone (1 microM) and dexamethasone (0.1 microM) abolished TNF-alpha- and TNF-beta-induced production of PGE2. In contrast to the cyclooxygenase inhibitors, the corticosteroids did not affect the stimulatory action by the cytokines on 45Ca release.(ABSTRACT TRUNCATED AT 250 WORDS)
Lerner
U H
UH
Department of Oral Cell Biology, University of Umeå, Sweden.
Ohlin
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015519:Bone Density / Q000187:drug effects; D001857:Bone Matrix / Q000187:drug effects; D001862:Bone Resorption / Q000503:physiopathology*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D046508:Culture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D015232:Dinoprostone; D002118:Calcium; D006854:Hydrocortisone