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Mutual Up-Regulation of Thyroid Hormone and Parathyroid Hormone Receptors in Rat Osteoblastic Osteosarcoma 17/2.8 Cells¹

Department of Molecular Pharmacology and Biological Chemistry (P.H.S., G.-G.D.) and Center for Endocrinology, Metabolism and Molecular Medicine (W.-X.G., L.D.M.), Northwestern University Medical School, Chicago, Illinois 60611-3008

Address all correspondence and requests for reprints to: Guo-Guang Du, M.D., Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611-3008. E-mail: g-du{at}nwu.edu

PTH and thyroid hormone (T₃) stimulate anabolic and catabolic processes in bone predominantly by acting on osteoblasts. Both inadequate and excessive secretion of either hormone can result in clinical bone disorders. In addition, T₃ and PTH related peptide (PTHrP) have multiple effects on a wide number of other tissues modulating both cell differentiation and proliferation. To address the question of whether there might be functional mutual regulation of T₃ receptors (TR) and PTH/PTHrP receptors (PTHR), we studied their expression and receptor-mediated intracellular effects in rat osteoblastic osteosarcoma (ROS) 17/2.8 cells. PTHR were up-regulated by T₃ pretreatment (10^-10–10^-6 M) in ROS 17/2.8 cells in a dose-dependent manner. T₃ pretreatment increased both PTH-induced cyclic AMP response element binding protein (CREB) phosphorylation and PTH-induced intracellular calcium transients, and further decreased PTH-induced down-regulation of alkaline phosphatase activity, suggesting that there are functional consequences of the PTHR up- regulation. Pretreatment with PTH (10^-10–10^-6 M) or PTHrP (10^-9 M) for 3–4 days resulted in a dose-dependent up-regulation of TR in ROS 17/2.8 cells. cAMP analogues or a calcium ionophore were able to mimic the effect of PTH on TR binding, suggesting that either the cAMP-signaling pathway or Ca²⁺ could be involved in PTH-induced up-regulation of the TR. These observations provide a novel example of mutual interactions between nuclear receptors and membrane receptors and may have significant implications for the regulation of bone remodeling in health and disease.

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