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Calcitonin-Dependent Down-Regulation of the Mouse C1a Calcitonin Receptor in Cells of the Osteoclast Lineage Involves a Transcriptional Mechanism¹

Departments of Cell Biology and Orthopedics and Yale Cancer Center, Yale University School of Medicine (D.I., C.S., W.C.H., R.B.), New Haven, Connecticut 06510; the Department of Biology and Anatomy, National Defense Medical Center (C.S.), Taipei, Taiwan 100, Republic of China; and the Department of Medicine, Harvard Medical School, New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine (D.L.G., S.R.G.), Boston, Massachusetts 02115-5716

Address all correspondence and requests for reprints to: Dr. Roland Baron, Department of Orthopedics, Yale University School of Medicine, P.O. Box 208044, New Haven, Connecticut 06520-8044. E-mail: roland.baron{at}yale.edu

Although expression of the calcitonin (CT) receptor (CTR) decreases after CT binding, there has been no evidence that it occurs at the transcriptional level. In the present study we investigated the mechanism of CTR messenger RNA (mRNA) down-regulation by CT in mouse cocultures of bone marrow and osteoblasts. Ribonuclease protection analysis revealed that osteoclast-like cells purified from cocultures predominantly express the C1a isoform and do not express an appreciable amount of the brain-specific C1b mRNA (<1% of C1a). Treatment of day 5 cocultures with CT caused a dose- and time-dependent decrease in the steady state level of C1a mRNA. This CT effect was mimicked by the cAMP agonists forskolin and (Bu)₂cAMP. Prolonged suppression of C1a mRNA was observed after short treatment with CT, but not with (Bu)₂cAMP, suggesting that persistent intracellular cAMP elevation is necessary for the prolonged CT effect. The half-life of the C1a mRNA in cocultures was 4–6 h and was not altered by CT or (Bu)₂cAMP. Moreover, competitive RT-PCR analysis revealed that 1-h treatment with CT reduced the level of CTR heterogeneous nuclear RNA to 10% in a cycloheximide-independent manner. These results suggest that CT down-regulates C1a-CTR mRNA expression at least in part by a transcriptional mechanism, thereby contributing to the ligand-induced desensitization in cells of the osteoclast lineage.

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