Endocrinology, Vol 137, 5213-5219, Copyright © 1996 by Endocrine Society

ARTICLES

Osteocalcin abnormalities in Hyp mice reflect altered genetic expression and are not due to altered clearance, affinity for mineral, or ambient phosphorus levels

TO Carpenter and CM Gundberg
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA. CarpenteTO@MASPO3.MAS.YALE.EDU

The Hyp mouse manifests rickets and renal wasting of phosphorus. We previously reported elevated circulating osteocalcin in Hyp mice, and a paradoxical decrease in response to 1,25-dihydroxyvitamin D3 [1,25- (OH)2D3]. To investigate these abnormalities further, we characterized in detail the response of circulating osteocalcin to 1,25-(OH)2D3 and compared skeletal osteocalcin in normal and Hyp mice. The affinity of osteocalcin for hydroxyapatite and the protein's clearance were compared in Hyp and normal animals. Finally, the response of osteocalcin messenger RNA (mRNA) to 1,25-(OH)2D3 was examined in normal mice, Hyp mice, and normal mice subjected to dietary phosphorus deprivation. Multiple (n = 3-6) daily doses of 1,25-(OH)2D3 are required to increase serum osteocalcin levels in normal C57 BL/6 mice; the effect is apparent by 6 h and persists for at least 24 h after injection. Single doses of up to 50 ng have no significant effect. In contrast, an approximately 50% decrement in circulating osteocalcin occurs after a single dose of 1,25-(OH)2D3 in Hyp mice. Osteocalcin clearance in Hyp mice appears to be normal. Bone osteocalcin per U calcium or phosphorus is normal in Hyp mice, suggesting that its affinity for hydroxyapatite is normal. Osteocalcin mRNA from Hyp mice is expressed in greater abundance than that from normal animals, reflecting the differences in circulating levels of the protein. Similarly, osteocalcin mRNA from Hyp mice decreases in response to 1,25- (OH)2D3, whereas an increase in osteocalcin message is seen in normal animals. These studies indicate that normal mice are relatively resistant to 1,25-(OH)2D3 stimulation of osteocalcin production. Furthermore, the differences between Hyp and normal mice in circulating osteocalcin reflect differences in the regulation of gene expression.

This article has been cited by other articles:

				M. B. Demay, Y. Sabbagh, and T. O. Carpenter Calcium and Vitamin D: What Is Known About the Effects on Growing Bone Pediatrics, March 1, 2007; 119(Supplement_2): S141 - S144. [Abstract] [Full Text] [PDF]

				D. Miao, X. Bai, D. Panda, M. D. McKee, A. C. Karaplis, and D. Goltzman Osteomalacia in Hyp Mice Is Associated with Abnormal Phex Expression and with Altered Bone Matrix Protein Expression and Deposition Endocrinology, February 1, 2001; 142(2): 926 - 939. [Abstract] [Full Text] [PDF]

				T. O. Carpenter, K. C. Moltz, B. Ellis, M. Andreoli, T. L. McCarthy, M. Centrella, D. Bryan, and C. M. Gundberg Osteocalcin Production in Primary Osteoblast Cultures Derived from Normal and Hyp Mice Endocrinology, January 1, 1998; 139(1): 35 - 43. [Abstract] [Full Text] [PDF]

				J. B. Lian, V. Shalhoub, F. Aslam, B. Frenkel, J. Green, M. Hamrah, G. S. Stein, and J. L. Stein Species-Specific Glucocorticoid and 1,25-Dihydroxyvitamin D Responsiveness in Mouse MC3T3-E1 Osteoblasts: Dexamethasone Inhibits Osteoblast Differentiation and Vitamin D Down-Regulates Osteocalcin Gene Expression Endocrinology, May 1, 1997; 138(5): 2117 - 2127. [Abstract] [Full Text] [PDF]