title: Tumor necrosis factor alpha modulates parathyroid hormone action in UMR-106-01 osteoblastic cells.
abstract: Tumor necrosis factor (TNF-alpha) has been shown to play an important role in local control of bone remodeling. The interaction of TNF-alpha and PTH was evaluated in UMR-106-01 cells, a phenotypic osteoblastic osteosarcoma cell line. We examined the influence of TNF-alpha on the two signal transduction systems triggered by PTH in UMR-106-01 cells, adenylate cyclase and free cytosolic calcium ([Ca2+]i). cAMP generation was inhibited in TNF-alpha-pretreated cells by 69, 61, 34, and 21% at PTH concentrations of 0.1, 1, 10, and 100 nM, respectively. Inhibition was seen at TNF-alpha doses of 100-1500 units/ml after a minimum incubation time of 12 h. TNF-alpha inhibition of the PTH-stimulated increase in [Ca2+]i was even more pronounced: treated cells showed no change in baseline [Ca2+]i after stimulation with 40 nM PTH. Treatment with TNF-alpha was also found to inhibit both arms of the PTH response in the nontransformed osteoblastic cell line, MC3T3-E1. TNF-alpha treatment did not alter cAMP generation in response to PGE2. TNF-alpha inhibition of the PTH-stimulated cAMP response was reversed completely by addition of cholera toxin (5 micrograms/ml) and partially by forskolin (10 microM) but not pertussis toxin (100 and 500 ng/ml). Scatchard analysis using PTHrP revealed that TNF-alpha treatment reduced the number of receptors but had no effect on KD. These findings suggest that TNF-alpha inhibits the osteoblastic response to PTH at least in part because of a reduction in receptor number. Further investigation is indicated to provide insight into the interaction of calciotropic hormones and cytokines in vivo.
authors.affiliation: Division of Pediatric Nephrology, Medical University of South Carolina, Charleston.
authors.forename: C D
authors.initials: CD
authors.lastname: Hanevold
authors.forename: D T
authors.initials: DT
authors.lastname: Yamaguchi
authors.forename: S C
authors.initials: SC
authors.lastname: Jordan
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D037342:Pertussis Toxin; D051381:Rats; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D010281:Parathyroid Hormone; D018016:Receptors, Parathyroid Hormone; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002118:Calcium