We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH) 2 D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1␣-hydroxylase (1␣(OH)ase ؊/؊ ) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25(OH) 2 D 3 , which normalized calcium in the 1␣(OH)ase ؊/؊ mice only; or 3) a "rescue" diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH) 2 D 3 but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH) 2 D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH) 2 D/VDR system. These studies indicate that the calcium ion and the 1,25(OH) 2 D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.Vitamin D plays a major role in modulating calcium and skeletal homeostasis and exerts a significant influence on the growth and differentiation of a variety of tissues (1-3). Vitamin D is absorbed from the diet and generated in skin by exposure to ultraviolet light. The secosteroid is transported in blood bound to vitamin D-binding protein (4)

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We examined parathyroid and skeletal function in 3-month-old mice expressing the null mutation for 25-hydroxyvitamin D-1a-hydroxylase [1a(OH)ase À/À ] and in mice expressing the null mutation for both the 1a(OH)ase and the calcium-sensing receptor [Casr À/À 1a(OH)ase À/À ] genes. On a normal diet, all mice were hypocalcemic, with markedly increased parathyroid hormone (PTH), increased trabecular bone volume, increased osteoblast activity, poorly mineralized bone, enlarged and distorted cartilaginous growth plates, and marked growth retardation, especially in the compound mutants. Osteoclast numbers were reduced in the Casr À/À 1a(OH)ase À/À mice. On a high-lactose, high-calcium, high-phosphorus ''rescue'' diet, serum calcium and PTH were normal in the 1a(OH)ase À/À mice but increased in the Casr À/À 1a(OH)ase À/À mice with reduced serum phosphorus. Growth plate architecture and mineralization were improved in both mutants, but linear growth of the double mutants remained abnormal. Mineralization of bone improved in all mice, but osteoblast activity and trabecular bone volume remained elevated in the Casr À/À 1a(OH)ase À/À mice. These studies support a role for calcium-stimulated maturation of the cartilaginous growth plate and mineralization of the growth plate and bone and calcium-stimulated CaSR-mediated effects on bone resorption. PTH-mediated bone resorption may require calcium-stimulated CaSR-mediated enhancement of osteoclastic activity. ß

A reader of the JBMR informed the editors about concern regarding a possible duplicate image in Fig. 3 in Richard and colleagues. (1) In consultation with the Committee on Publication Ethics (COPE) guidelines, the editors sought an explanation from the authors for this possible panel duplication.In Richard and colleagues, (1) the authors acknowledge an error made in presenting the images in Fig. 3B, with an image and a partial enlargement appearing in two panels, but were unable to ascertain the source of the duplication. The authors provided an alternate version of Fig. 3 (below). The authors note that osteoid was determined with von Kossa staining (shown in Fig. 3A) as well as with the Fig. 3. ERRATUM