Tumor necrosis factor α modulates parathyroid hormone action in UMR-106–01 osteoblastic cells

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Abstract
Tumor necrosis factor (TNF-α) has been shown to play an important role in local control of bone remodeling. The interaction of TNF-α and PTH was evaluated in UMR-106–01 cells, a phenotypic osteoblastic osteosarcoma cell line. We examined the influence of TNF-α 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-α-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-α doses of 100–1500 units/ml after a minimum incubation time of 12 h. TNF-α inhibition of the PTH-stimulated increase in [Ca2+], was even more pronounced: treated cells showed no change in baseline [Ca2+]i, after stimulation with 40 nM PTH. Treatment with TNF-α was also found to inhibit both arms of the PTH response in the nontransformed osteoblastic cell line, MC3T3-El. TNF-α treatment did not alter cAMP generation in response to PGE2. TNF-α inhibition of the PTH-stimulated cAMP response was reversed completely by addition of cholera toxin (5 μg/ml) and partially by forskolin (10 μM) but not pertussis toxin (100 and 500 ng/ml). Scatchard analysis using PTHrP revealed that TNF-α treatment reduced the number of receptors but had no effect on KD. These findings suggest that TNF-α 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.
Funding Information
  • National Research Service Award (1F32GM3515-01)
  • Career Development Award and Medical Research

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