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Endocrinology Vol. 140, No. 11 4982-4987
Copyright © 1999 by The Endocrine Society

ARTICLES

Rescue of the Skeletal Phenotype of Vitamin D Receptor-Ablated Mice in the Setting of Normal Mineral Ion Homeostasis: Formal Histomorphometric and Biomechanical Analyses1

Michael Amling, Matthias Priemel, Timothy Holzmann, Kelli Chapin, Johannes M. Rueger, Roland Baron and Marie B. Demay

Department of Trauma Surgery, Hamburg University School of Medicine (M.A., M.P., T.H., J.M.R.), Hamburg, Germany; the Department of Cell Biology, Yale University School of Medicine (M.A., R.B.), New Haven, Connecticut 06510; and the Endocrine Unit, Massachusetts General Hospital, Harvard Medical School (K.C., M.B.D.), Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Marie Demay, Endocrine Unit, Wellman 501, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: demay{at}helix.mgh.harvard.edu

1,25-Dihydroxyvitamin D3 has been shown to play an important role in vitro in regulating osteoblast gene transcription and promoting osteoclast differentiation. To address the role of the vitamin D receptor (VDR) in skeletal homeostasis, formal histomorphometric analyses were performed in VDR null mice in the setting of impaired mineral ion homeostasis as well as in VDR null mice in whom normal mineral ion homeostasis had been preserved. In hypocalcemic VDR null mice, there was an increase in bone volume as a result of a dramatic increase in osteoid. There was also an increase in the number of osteoblasts without a significant change in the number of osteoclasts. Examination of the growth plate revealed marked disorganization, with an increase in vascularity and matrix. Biomechanical parameters demonstrated increased bone fragility in the hypocalcemic VDR null mice.

In the VDR ablated mice in whom normal mineral ion homeostasis had been preserved, none of these measurements was significantly different from those in wild-type littermates raised under identical conditions. Notably, the morphology and width of the growth plate were indistinguishable from those in wild-type controls, demonstrating that a calcium/phosphorus/lactose-enriched diet started at 16 days of age in the VDR null mice permits the development of both normal morphology in the growth cartilage and adjacent metaphysis and normal biomechanical competence of cortical bone. Thus, the principle action of the VDR in skeletal growth, maturation, and remodeling is its role in intestinal calcium absorption. The skeletal consequences of VDR ablation are a result of impaired intestinal calcium absorption and/or the resultant secondary hyperparathyroidism and hypophosphatemia.




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