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Induction of the Vitamin D 24-Hydroxylase (CYP24) by 1,25-Dihydroxyvitamin D₃ Is Regulated by Parathyroid Hormone in UMR106 Osteoblastic Cells¹

Geriatric Research, Education and Clinical Center (H.J.A., T.L.H., M.A.B., V.B.K.), St. Louis VA Medical Center, St. Louis, Missouri 63125; Division of Geriatric Medicine (H.J.A., T.L.H., M.A.B., V.B.K.), Department of Biochemistry and Molecular Biology (H.J.A.), Department of Pharmacological and Physiological Science (N.C.P.), St. Louis University Health Sciences Center, St. Louis, Missouri 63104; and Renal Division (A.J.B.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: H. J. Armbrecht, Ph.D., Geriatric Center (11G-JB), St. Louis VA Medical Center, St. Louis, Missouri 63125.

The expression of the vitamin D 24-hydroxylase is highly regulated in target tissues for 1,25-dihydroxyvitamin D₃ (1, 25(OH)₂D), where it may modulate the action of 1,25(OH)₂D. In UMR106 osteoblastic cells, 1,25(OH)₂D and PTH synergistically induce 24-hydroxylase expression. The purpose of these studies was to characterize the interaction between 1,25(OH)₂D and PTH with regard to the messenger RNA (mRNA) levels of the cytochrome P450 component of the 24-hydroxylase (CYP24). PTH alone had no effect on CYP24 mRNA levels, and 1,25(OH)₂D alone produced only a modest increase. However, 1,25(OH)₂D and PTH together synergistically increased CYP24 mRNA levels 3-fold compared with 1,25(OH)₂D alone. PTH also increased the sensitivity of UMR cells to 1,25(OH)₂D from 10^-8 to 10^-10 M. PTH worked through the cAMP signaling pathway as evidenced by the lack of effect of PTH (3–34) and by the full activity of 8-bromo-cAMP. PTH in the presence of 1,25(OH)₂D increased CYP24 gene transcription as shown by nuclear run-on studies and by activation of a CYP24 promoter-reporter construct after transfection. PTH also increased vitamin D receptor number in UMR cells, but this occurred at times later than the increase in transcription. These studies demonstrate that PTH in the presence of 1,25(OH)₂D works through the cAMP-dependent signaling pathway to increase transcription of the CYP24 gene, to increase CYP24 protein levels, and to increase 24-hydroxylase activity.

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