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Normalization of Mineral Ion Homeostasis by Dietary Means Prevents Hyperparathyroidism, Rickets, and Osteomalacia, But Not Alopecia in Vitamin D Receptor-Ablated Mice¹

Endocrine Unit, Massachusetts General Hospital, Harvard Medical School (Y.C.L., A.E.P., J.M., M.B.D.), Boston, Massachusetts 02114; the Department of Cell Biology, Yale University School of Medicine (M.A., R.B.), New Haven, Connecticut 06510; and the Department of Bone Pathology, Hamburg University School of Medicine (M.A., M.P., G.D.), 20246 Hamburg, Germany

Address all correspondence and requests for reprints to: Marie B. Demay, M.D., Endocrine Unit, Massachusetts General Hospital, Wellman 501, 32 Fruit Street, Boston, Massachusetts 02114. E-mail: demay{at}helix.mgh.harvard.edu

	Abstract

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1,25-Dihydroxyvitamin D₃ plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorption rather than receptor deficiency, mineral ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum ionized calcium levels in the VDR-ablated mice. The correction of ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalization of mineral ion homeostasis can prevent the development of hyperparathyroidism, osteomalacia, and rickets in the absence of the genomic actions of 1,25-dihydroxyvitamin D₃.

	Introduction

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ONE OF THE major physiological roles of 1,25-dihydroxyvitamin D₃, the most active hormonal form of vitamin D, is to maintain mineral ion homeostasis (1). Animal studies have demonstrated that vitamin D deficiency results in hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia (2, 3, 4) despite the presence of detectable levels of vitamin D and its active metabolite, 1,25-dihydroxyvitamin D. The hereditary human disorder vitamin D-dependent rickets type II (VDDRII; also known as hereditary vitamin D-resistant rickets), caused by mutations in the vitamin D receptor (VDR), is characterized by these abnormalities and, in some kindreds, is associated with alopecia (5, 6, 7). The presence of alopecia in VDDRII is thought by some investigators to be associated with a more severe clinical phenotype (8). 1,25-Dihydroxyvitamin D₃ has been shown to play a critical role in intestinal calcium absorption, but the analysis of the pathophysiology of the other abnormalities observed in vitamin D deficiency is complicated by difficulties in differentiating the effects of hormone deficiency from those of impaired mineral ion homeostasis. Studies in vitamin D-deficient animals have suggested that normal levels of vitamin D are not required for neonatal skeletal development or for mineralization of osteomalacic lesions (3, 9, 10). Direct actions of vitamin D on osteoblasts, osteoclasts, and bone matrix protein synthesis in vitro are well established (11, 12, 13, 14). In addition to bony abnormalities, rachitic changes are seen in vitamin D deficiency. These disorganized growth plates are also observed in hypophosphatemic rickets, where affected individuals are normocalcemic. It has been unclear to what extent the abnormal organization observed in the growth plates in rickets is a reflection of hypophosphatemia, hypocalcemia, secondary hyperparathyroidism, or vitamin D deficiency. 1,25-Dihydroxyvitamin D₃ is thought to be an important regulator of PTH gene expression and parathyroid cell proliferation (15, 16). It has not been established, however, to what extent the parathyroid abnormalities observed in vitamin D-deficient animals are due to impaired mineral ion homeostasis or to hormone deficiency per se.

We have generated an animal model of VDDRII by targeted disruption of the second zinc finger of the VDR gene in mice. The phenotype is identical to that of the human disease, including the development of progressive alopecia (17). Similar observations were made by others in VDR-ablated mice with disruption of the first zinc finger. However, minimal alopecia was found in these mice, perhaps because of their decreased survival (18). To distinguish the effects of VDR ablation from those of impaired mineral ion homeostasis on the development of the phenotype, the VDR-ablated mice and control littermates were placed on a 20% lactose, 2% calcium, 1.25% phosphorus diet. This diet has previously been shown to prevent hypocalcemia and an increase in serum PTH levels in vitamin D-deficient rats (4).

	Materials and Methods

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Animal maintenance
All studies performed were approved by the institutional animal care committee. VDR null mice (17) and control littermates were maintained in a virus- and parasite-free barrier facility and exposed to a 12-h light, 12-h dark cycle. The mice were fed autoclaved Purina rodent chow (5010, Ralston-Purina, St. Louis, MO) containing 1% calcium, 0.67% phosphorus, 0% lactose, and 4.4 IU vitamin D/g (regular diet). To normalize the blood mineral ion levels of the VDR-ablated mice, the animals were fed a -irradiated test diet (TD96348, Teklad, Madison, WI) containing 2% calcium, 1.25% phosphorus, and 20% lactose supplemented with 2.2 IU vitamin D/g from 19 days of age.

Serum parameters
Ionized calcium levels were determined using a Ciba/Corning 634 Ca²⁺/pH analyzer. Intact PTH levels were determined using a two-site immunoradiometric assay kit (Nichols Institute Diagnostics, San Juan Capistrano, CA) for rat PTH. Serum phosphorus determinations were performed at the Tufts Veterinary Laboratory (Grafton, MA).

Tissue histology
Tissues were routinely fixed overnight in 4% formaldehyde in PBS (pH 7.2), processed, embedded in paraffin, and cut into 6-µm sections with a Leica RM 2025 microtome (Leica, Deerfield, IL). The skin specimens were obtained from the middorsum. The thyroids, parathyroids, trachea, and heart were removed en bloc to facilitate orientation and sectioning in the same plane. Serial sections through the entire parathyroid gland were obtained. Sections with the greatest parathyroid diameter were chosen for experiments. The volume of parathyroid glands was estimated by the number of 6-µm sections in which the glands were visualized and the diameter of the glands on these sections.

The femur, tibia, and fibula were dissected and fixed in 4% formaldehyde for 18 h at 4 C. Contact radiography was performed with FaxitronContact (Faxitron, Munich, Germany). The undecalcified bones were embedded in methylmethacrylate, and 5-µm sections were prepared on a rotation microtome (Jung, Heidelberg, Germany) as previously described (19). Sections were stained with toluidine blue or Von Kossa and evaluated using a Zeiss microscope (Carl Zeiss, Jena, Germany).

In situ hybridization
In situ hybridization of the parathyroid glands was performed using an [³⁵S]UTP-labeled PTH complementary RNA probe as described previously (17).

Immunostaining
Proliferating cell nuclear antigen (PCNA) staining of the parathyroid glands was performed using a PCNA Staining Kit (Zymed Laboratories, South San Francisco, CA) following the manufacturer’s instruction. PCNA-positive cells were counted and expressed as positive cells per square arbitrary unit. Quantitative data were obtained from at least four gland sections derived from two animals.

Statistical analyses
Data are presented as the mean ± SEM. Student’s unpaired t test was used to identify significant differences (P < 0.05).

	Results

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The VDR-ablated mice are indistinguishable from their wild-type and heterozygous littermates until 21 days of age, when they develop hypocalcemia, hypophosphatemia, hyperparathyroidism, growth retardation, and alopecia (17). To determine whether the high calcium, high phosphorus, high lactose diet could prevent the development of these abnormalities, the receptor-ablated mice were placed on this diet at 19 days of age, when their calcium and PTH levels were still normal. As shown in Fig. 1, the receptor-ablated mice fed this test diet maintained ionized calcium levels indistinguishable from those of their control littermates fed the same diet (Fig. 1A, squares and diamonds). In contrast, consistent with our previous findings (17), the receptor-ablated mice fed regular lab chow develop hypocalcemia (Fig. 1A, circles). The rescue diet also prevented the development of hypophosphatemia in the receptor-ablated mice (Fig. 1B). The receptor-ablated mice fed the test diet had a growth curve indistinguishable from that of their control littermates fed the same diet (Fig. 1C, squares and diamonds) in contrast to that of animals fed regular chow (Fig. 1C, circles) (17). None of these parameters was affected by diet in the control mice.

View larger version (21K): [in this window] [in a new window]   Figure 1. Serum chemistries and growth curve. A, Serum ionized calcium levels in mice receiving the regular and test diets. Ionized calcium concentrations were determined using blood obtained by tail nicking and normalized to pH 7.4. Values are presented as the mean ± SEM of four to seven mice. The absence of error bars indicates points where the SEM is less than 0.6. The calcium levels of the wild-type (not shown), heterozygous (squares), and homozygous (diamonds) mice fed the test were not significantly different, whereas the homozygous mice fed regular chow (circles) were hypocalcemic. *, P < 0.001 compared with homozygous mice on the test diet. B, Serum phosphorus concentration in mice receiving the regular and test diets at 70 days of age. Values are obtained from four or five wild-type (closed bars) and homozygous (open bars) mice and are presented as the mean ± SEM. *, P < 0.02 compared with wild-type mice receiving the regular diet. C, Growth curve of mice receiving the regular and test diets. Each point represents the mean body weight ± SEM of four to seven male mice. The wild-type (not shown), heterozygous (squares), and homozygous (diamonds) mice fed the test diet had similar values, whereas the homozygous mice fed the regular diet (circles) weighed significantly less. *, P < 0.01; **, P < 0.02 (compared with homozygous mice receiving the test diet).

View larger version (72K): [in this window] [in a new window]   Figure 2. Parathyroid glands and PTH mRNA synthesis. Parathyroid gland sections were stained with hematoxylin and eosin and hybridized in situ with a PTH complementary RNA probe (brightfield, A, C, and E; darkfield, B, D, and F). The parathyroid glands were obtained from 70-day-old wild-type (A and B) and homozygous (C and D) mice fed the regular diet and from homozygous (E and F) mice fed the test diet. This data are representative of those obtained from two to four mice of each genotype.

View larger version (47K): [in this window] [in a new window]   Figure 3. Parathyroid cell proliferation. Parathyroid gland sections were immunostained with an antibody against PCNA as described in Materials and Methods. The parathyroid glands were obtained from 35-day-old wild-type (A) and homozygous (B) mice fed the regular diet and from homozygous mice fed the test diet (C).

View larger version (116K): [in this window] [in a new window]   Figure 4. Contact radiography (A, B, E, and F) and toluidine blue staining (C, D, G, and H) of the tibia from 70-day-old littermates. Tibias were obtained from wild-type (A and C) and homozygous (B and D) mice fed the regular diet and from wild-type (E and G) and homozygous (F and H) mice fed the test diet. These data are representative of those found in four mice of each genotype.

View larger version (146K): [in this window] [in a new window]   Figure 5. Toluidine blue staining of metaphysis of 70-day-old mice. Tibias were obtained from wild-type (A) and homozygous (B) mice fed regular diet and from wild-type (C) and homozygous (D) mice fed the test diet. These data are representative of those found in four mice of each genotype.

View larger version (45K): [in this window] [in a new window]   Figure 6. Hematoxylin and eosin staining of the skin from a 70-day-old wild-type (A) and a homozygous (B) mouse fed the regular diet and from a homozygous mouse fed the test diet (C).

	Discussion

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Secondary hyperparathyroidism, characterized by an increase in serum PTH levels, occurs in association with hypocalcemia, chronic vitamin D deficiency, or renal insufficiency. In vitro studies using dispersed parathyroid cells demonstrate that 1,25-dihydroxyvitamin D₃ suppresses PTH secretion and its mRNA synthesis (22, 23, 24, 25), as does high calcium concentration in the medium (26, 27). Animal studies confirm that 1,25-dihydroxyvitamin D₃ directly inhibits (16) and hypocalcemia stimulates (28, 29) PTH mRNA synthesis in vivo. Therefore, in vitamin D-deficient animals, it is not clear whether the development of hyperparathyroidism is due to the lack of 1,25-dihydroxyvitamin D₃ actions, hypocalcemia, or a combination of both. Our data demonstrate that normalization of blood ionized calcium levels in VDR-ablated mice prevents the development of secondary hyperparathyroidism and parathyroid cell proliferation, strongly suggesting that blood calcium, rather than 1,25-dihydroxyvitamin D₃ itself, plays a key role in the pathogenesis of hyperparathyroidism. It is possible, however, that in the presence of normal serum calcium levels, 1,25-dihydroxyvitamin D₃ is not required, and that 1,25-dihydroxyvitamin D₃ plays a role only in the setting of hypocalcemia. This is consistent with the observation that rats maintained on a vitamin D-deficient diet become hyperparathyroid only when calcium is restricted (30) and supports the finding that hyperparathyroidism can be prevented by dietary means in rats with low vitamin D and 1,25-dihydroxyvitamin D levels (4).

Vitamin D deficiency and VDR mutations in humans result in rickets and osteomalacia. In vitro studies suggest that 1,25-dihydroxyvitamin D₃ plays an important role in the regulation of osteoblast and osteoclast activity as well as in the regulation of bone matrix protein synthesis. Acute administration of pharmacological doses of 1,25-dihydroxyvitamin D₃ in vivo results in a transient augmentation of osteoclast activity and recruitment (31). 1,25-Dihydroxy-vitamin D₃ directly modulates osteoblast proliferation and osteoblastic gene expression (32), including -I collagen, alkaline phosphatase, osteocalcin, and osteopontin (11, 12, 13, 14). However, when vitamin D-deficient rats are infused with calcium and phosphate, healing of osteomalacic lesions is observed, suggesting that vitamin D is not essential for bone mineralization (3, 10). Curing of osteomalacic lesions by calcium infusion has also been documented in a patient with VDDRII (33). Consistent with the hypothesis that 1,25-dihydroxyvitamin D is not required for mineralization, formal histomorphometric analyses have demonstrated that the rescue diet prevents the development of osteomalacia in the VDR-ablated mice (41, 42).

In addition to bony abnormalities, rachitic changes are observed in vitamin D-deficient animals and in humans with VDR mutations. Disorganized growth plates are also observed in hypophosphatemic rickets, where the affected individuals are normocalcemic. It remains unclear, therefore, to what extent the growth plate abnormalities observed in vitamin D deficiency are secondary to hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, or vitamin D deficiency per se. The prevention of rachitic changes by dietary intervention in the VDR-ablated mice demonstrates that the receptor-dependent actions of 1,25-dihydroxyvitamin D are not required for normal growth plate development or maturation. These data, rather, suggest that impaired mineral ion homeostasis or the resultant secondary hyperparathyroidism are the primary causes of the rachitic changes. Further investigations are required to discern which of these factors plays the key etiological role.

The VDR is expressed in the outer root sheath and the bulb of hair follicles as well as in sebaceous glands (34, 35). In vitro studies have shown that 1,25-dihydroxyvitamin D₃ modulates keratinocyte proliferation and differentiation (36), but the role of vitamin D or the VDR in hair growth is not understood. The association of VDR gene mutations with alopecia in both humans (37) and mice (17) and the observation that VDR expression is differentially regulated during distinct stages of the hair cycle (34), strongly suggest that the VDR plays an important role in the hair cycle. The VDR-ablated mice develop alopecia regardless of their mineral ion status, suggesting that mutation of the receptor per se, rather than hypocalcemia, is directly responsible for the hair loss. The absence of alopecia in profound vitamin D deficiency and in patients with VDDRI, characterized by mutations in the 25-hydroxyvitamin D-1-hydroxylase gene (38, 39), further supports the hypothesis that the pathogenesis of alopecia is a consequence of receptor deficiency rather than of ligand deficiency. Thus, it is possible that the VDR has ligand-independent effects in the epidermis, either directly regulating gene transcription or modulating the effects of other transcriptional regulators such as the closely related retinoic acid and retinoid-X receptors, which have been shown to inhibit effects of 1,25-dihydroxyvitamin D on keratinocyte differentiation (40). Alternatively, ligand-receptor interactions may be essential for normal hair growth, with locally synthesized vitamin D metabolites being responsible for the maintenance of normal skin homeostasis in settings of profound systemic 1,25-dihydroxyvitamin D deficiency. Clarification of the molecular basis for the effects of the VDR on keratinocytes will add a new dimension to our understanding of the physiological actions of 1,25-dihydroxyvitamin D₃ and its nuclear receptor.

	Footnotes

 
¹ This work was supported by NIH Grants DK-46974 (to M.B.D.) and DE-04724 (to R.B.) and a NIH National Research Service Award (to Y.C.L.).

Received March 31, 1998.

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