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PubMed1992

The occurrence of interglobular dentin in incisors of hypophosphatemic mice fed a high-calcium and high-phosphate diet.

The incisor dentin of hypophosphatemic (Hyp) mice was examined histopathologically to determine whether the multiple occurrences of interglobular dentin would be influenced by the serum phosphate level. Both normal and Hyp mice (12 weeks of age) were divided into two groups. The mice in one group were given a control diet (1.42% Ca, 1.16% P) and the other a high-calcium and high-phosphate diet (2.00% Ca, 3.00% P) for 30 days. Blood was collected from the mice every fifth day for measurement of the calcium and phosphate concentrations in serum. Both ground and decalcified cross-sections were prepared from incisors from the mandible and maxilla for microscopic examination. The levels of serum Ca and P were almost constant in normal mice, regardless of diet. On the other hand, serum P levels in Hyp mice fed the control diet were significantly lower than those in normal mice. The ten days' feeding of the high-Ca/-P diet significantly elevated the serum P level in Hyp mice, and it reached a level similar to that of the normal mice. However, histopathological examination showed no significant changes in incisor dentin of Hyp mice fed the high-Ca/-P diet, and interglobular dentin still occurred. These results suggest that the multiple formations of interglobular dentin, which is the most outstanding feature of X-linked hypophosphatemic vitamin-D-resistant rickets, are not influenced in Hyp mice by the short-time normalization of the serum phosphate level.

Animals↗
PubMed2005

Hyper-expression of osteocalcin mRNA in odontoblasts of Hyp mice.

The Hyp mouse is a murine homologue of human X-linked hypophosphatemia that displays hypo-mineralization in bone and dentin. In this study, we tested the hypothesis that the defect in Hyp mice leads to alterations in the expression of dentin matrix proteins that may be associated with the hypo-mineralization changes in the tissues. Quantitative RT-PCR analyses showed that expression of the osteocalcin gene in Hyp mice tooth germ samples was significantly higher than in wild-type mice, whereas the gene expressions of osteonectin, osteopontin, dentin matrix protein 1, and type I collagen in both types of mice were similar. Further, cultured Hyp mice tooth germ samples exhibited a higher expression of the osteocalcin gene than did those from wild-type mice, which was in accord with the results of our in vivo analysis. These findings suggest that osteocalcin mRNA is highly expressed in Hyp mice odontoblasts and may be associated with dentin hypo-mineralization.

Animals↗
PubMed2004

The wrickkened pathways of FGF23, MEPE and PHEX.

The last 350 years since the publication of the first medical monograph on rickets (old English term wrickken) (Glisson et al., 1651) have seen spectacular advances in our understanding of mineral-homeostasis. Seminal and exciting discoveries have revealed the roles of PTH, vitamin D, and calcitonin in regulating calcium and phosphate, and maintaining healthy teeth and skeleton. However, it is clear that the PTH/Vitamin D axis does not account for the entire picture, and a new bone-renal metabolic milieu has emerged, implicating a novel set of matrix proteins, hormones, and Zn-metallopeptidases. The primary defects in X-linked hypophosphatemic rickets (HYP) and autosomal-dominant hypophosphatemic rickets (ADHR) are now identified as inactivating mutations in a Zn-metalloendopeptidase (PHEX) and activating mutations in fibroblast-growth-factor-23 (FGF23), respectively. In oncogenic hypophosphatemic osteomalacia (OHO), several tumor-expressed proteins (MEPE, FGF23, and FRP-4) have emerged as candidate mediators of the bone-renal pathophysiology. This has stimulated the proposal of a global model that takes into account the remarkable similarities between the inherited diseases (HYP and ADHR) and the tumor-acquired disease OHO. In HYP, loss of PHEX function is proposed to result in an increase in uncleaved full-length FGF23 and/or inappropriate processing of MEPE. In ADHR, a mutation in FGF23 results in resistance to proteolysis by PHEX or other proteases and an increase in half-life of full-length phosphaturic FGF23. In OHO, over-expression of FGF23 and/or MEPE is proposed to result in abnormal renal-phosphate handling and mineralization. Although this model is attractive, many questions remain unanswered, suggesting a more complex picture. The following review will present a global hypothesis that attempts to explain the experimental and clinical observations in HYP, ADHR, and OHO, plus diverse mouse models that include the MEPE null mutant, HYP-PHEX transgenic mouse, and MEPE-PHEX double-null-mutant.

Animals↗
PubMed1975

1,25-dihydroxyvitamin D3 and 1, alpha-hydroxyvitamin D3 in children: biologic and therapeutic effects in nutritional rickets and different types of vitamin D resistance.

This investigation confirms the high level of biologic activity and the similarity of the effects of small doses of 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3) and of its analog 1alpha-hydroxyvitamin D3 (1alpha-OH-D3) on children with nutritional rickets, "pseudodeficiency" rickets (PDR), hereditary hypophosphatemia, chronic idiopathic hypoparathyroidism, and chronic renal failure. It also shows that cystinotic patients may develop, at the end stage of the disease, a certain degree of resistance to 1,25-(OH)2-D3. The comparison of the therapeutic effects of long term oral administration of 1,25-(OH)2-D3 or 1alpha-OH-D3 to two D-deficient children and two sibs with PDR demonstrates differences in sensitivity. In the patients with nutritional rickets, 0.5 mug/24 hr of either drug corrects the biochemical abnormalities, initiates healing of skeletal lesions in 28 days, and cures the metaphyseal le lesions in 60 days of therapy. In contrast, it appears that doses of either drug that are curative in D deficiency rickets are only partly active in PDR. These observations indicate that the hypothesis of a deficit in 25-hydroxycholecalciferol 1alpha-hydroxylase in patients with PDR must await for confirmation more direct evidences, and that such a deficit, even if proven, may not account for all of the biochemical and skeletal alterations seen in patients with this inherited disorder.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1998

Genetic screening for X-linked hypophosphatemic mice and ontogenic characterization of the defect in the renal sodium-phosphate transporter.

X-linked hypophosphatemic (Hyp) rickets is characterized by short stature, rickets, and bone abnormalities. Biochemically, hypophosphatemia and decreased renal reabsorption of phosphate are the hallmark of the disorder. Mutation of the PEX gene has been linked to human and murine Hyp rickets. Our study showed that phenotypical changes of this disease could be detected in 6-wk-old mice, but not in 2-wk-old mice. Therefore, we developed a PCR method to identify Hyp mice by detecting a lack of the 3' region of the PEX gene. Serum inorganic phosphate (Pi) levels were decreased, whereas alkaline phosphatase activity was increased in 2- and 6-wk-old Hyp mice. Northern blot showed that renal Na(+)-Pi transporter mRNA levels were decreased by 2.1-fold (1.47 +/- 0.21 densitometric units for normals; 0.68 +/- 1.43 for Hyp mice; p < 0.040) in 2-wk-old Hyp mice and by 1.7-fold (2.41 +/- 0.42 for normals; 1.44 +/- 0.33 for Hyp mice; p < 0.027) in 6-wk-old mice. Western blot showed that levels of immunoreactive renal Na(+)-Pi transporter protein were decreased by 4.5-fold (0.90 +/- 0.10 for normals; 0.22 +/- 0.08 for Hyp mice; p < 0.001) in 2-wk-old Hyp mice; and by 4.9-fold (1.47 +/- 0.19 for normals; 0.30 +/- 0.09 for Hyp mice; p < 0.0001) in 6-wk-old Hyp mice. In addition, levels of Na(+)-Pi transporter mRNA and protein were increased between 2- and 6-wk-old normal mice, but not in Hyp mice. This study demonstrates an easy assay to detect Hyp mutation and characterizes the defect during ontogeny of the Na(+)-Pi transporter in Hyp mice.

Alkaline Phosphatase↗
PubMed2003

Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice.

X-linked hypophosphatemic (Hyp) mice exhibit hypophosphatemia, impaired renal phosphate reabsorption, defective skeletal mineralization, and disordered regulation of vitamin D metabolism: In Hyp mice, restriction of dietary phosphorus induces a decrease in serum concentration of 1,25-dihydroxyvitamin D and renal activity of 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase), and induces an increase in renal activity of 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase). In contrast, in wild-type mice, phosphorus restriction stimulates renal 1alpha-hydroxylase gene expression and suppresses that of 24-hydroxylase. To determine the molecular basis for the disordered regulation of vitamin D metabolism in Hyp mice, we determined renal mitochondrial 1alpha-hydroxylase activity and the renal abundance of p450c1alpha and p450c24 mRNA in wild-type and Hyp mice fed either control, low-, or high-phosphorus diets for 5 d. In wild-type mice, phosphorus restriction increased 1alpha-hydroxylase activity and p450c1alpha mRNA expression by 6-fold and 3-fold, respectively, whereas in the Hyp strain the same diet induced changes of similar magnitude but opposite in direction. Phosphorus supplementation was without effect in wild-type mice, whereas in Hyp mice the same diet induced 3-fold and 2-fold increases, respectively, in enzyme activity and p450c1alpha mRNA abundance. In wild-type mice, both renal 1alpha-hydroxylase activity and p450c1alpha mRNA abundance varied inversely and significantly with serum phosphorus concentrations, whereas in Hyp mice the relationship between both renal parameters and serum phosphorus concentration was direct. In Hyp mice, phosphorus restriction induced a significant increase in renal p450c24 mRNA abundance, in contrast to the lack of effect observed in wild-type mice. The present findings demonstrate that regulation of both the p450c1alpha and p45024 genes by phosphorus is disordered in Hyp mice at the level of renal 1alpha-hydroxylase activity and renal p450c1alpha and p450c24 mRNA expression.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse.

Hyp-mice exhibit abnormal regulation of 25-hydroxyvitamin D [25(OH)D]-1alpha-hydroxylase activity. Previous observations suggest such aberrant modulation is posttranscriptional. To investigate this possibility further, we examined whether hyp-mice manifest abnormal translation of 25(OH)D-1alpha-hydroxylase mRNA. We compared phosphate, parathyroid, and calcitonin effects on renal 25(OH)D-1alpha-hydroxylase protein as well as mRNA and enzyme activity in normal and hyp-mice. We assayed protein by Western blots, mRNA by real-time RT-PCR, and enzyme activity by measuring 1,25-dihydroxyvitamin D production. Although phosphate-depleted mice exhibited enhanced enzyme function, with significantly increased mRNA and protein expression, hyp-mice comparably increased mRNA but failed to augment enzyme activity, concordant with an inability to increase protein expression. PTH stimulation increased mRNA and protein expression as well as enzyme activity in normal mice but in hyp-mice, despite effecting mRNA enhancement, did not increment enzyme function or protein. The inability of hypophosphatemia and PTH to increase 25(OH)D-1alpha-hydroxylase activity and protein expression in hyp-mice was not universal because calcitonin stimulation was normal, suggesting proximal convoluted tubule localization of the defect. These data, in accord with absent undue enhancement of protein expression in hyp-mice treated with protease inhibitors, establish that abberrant regulation of vitamin D metabolism results from abnormal translational activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders.

Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D(3)) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D(3) production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.

Animals↗
PubMed2005

Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice.

Fibroblast growth factor-23 (FGF-23) is a novel circulating peptide that regulates phosphorus (Pi) and vitamin D metabolism, but the mechanisms by which circulating FGF-23 itself is regulated are unknown. To determine whether the serum FGF-23 concentration is regulated by dietary intake of Pi, we fed wild-type (WT), Npt2a gene-ablated (Npt2a(-/-)), and Hyp mice diets containing varying Pi contents (0.02-1.65%). In WT mice, increases in dietary Pi intake from 0.02-1.65% induced a 7-fold increase in serum FGF-23 and a 3-fold increase in serum Pi concentrations. Across the range of dietary Pi, serum FGF-23 concentrations varied directly with serum Pi concentrations (r(2) = 0.72; P < 0.001). In Npt2a(-/-) mice, serum FGF-23 concentrations were significantly lower than in WT mice, and these differences could be accounted for by the lower serum Pi levels in Npt2a(-/-) mice. The serum concentrations of FGF-23 in Hyp mice were 5- to 25-fold higher than values in WT mice, and the values varied with dietary Pi intake. Fgf-23 mRNA abundance in calvaria was significantly higher in Hyp mice than in WT mice on the 1% Pi diet; in both groups of mice, fgf-23 mRNA abundance in calvarial bone was suppressed by 85% on the low (0.02%) Pi diet. In WT mice fed the low (0.02%) Pi diet, renal mitochondrial 1alpha-hydroxylase activity and renal 1alpha-hydroxylase (P450c1alpha) mRNA abundance were significantly higher than in mice fed the higher Pi diets and varied inversely with serum FGF-23 concentrations (r(2) = 0.86 and r(2) = 0.64; P < 0.001, respectively). The present data demonstrate that dietary Pi regulates the serum FGF-23 concentration in mice, and such regulation is independent of phex function. The data suggest that genotype-dependent and dietary Pi-induced changes in the serum FGF-23 concentration reflect changes in fgf-23 gene expression in bone.

Animals↗
PubMed1980

Abnormal vitamin D metabolism in the X-linked hypophosphatemic mouse.

The vitamin D metabolites, 25-hydroxyvitamin D (250HD) and 1,25-dihydroxyvitamin D [1,25-(OH)2D], were measured in samples of plasma from normal and X-linked hypophosphatemic (Hyp) mice, which are a model for this common form a human vitamin D-resistant rickets. Each sample was the pooled plasma from the exsanguination of 10-15 mice. On stock diets plasma 1,25-(OH)2D was the same in Hyp mice as in normal mice [normal vs. Hyp, 70 +/- 4 vs. 66 +/- 4 pM; (mean +/- SE) n = 8; P = NS]. However, plasma 25OHD was lower in Hyp mice (59 +/- 4 vs. 37 +/- 4 nM; n = 6; P < 0.01). Since hypophosphatemia usually elevates plasms 1,25-(OH)2D in rats, we suspected that Hyp mice were unresponsive to hypophosphatemia. To test this, mice were challenged with a low phosphorus (P) diet for 6 days . A low P diet lowered plasma P and raised plasma calcium levels in both normal and Hyp mice. In both genotypes, the low P diet also increased magnesium levels in urine and transiently in plasma. The low P diet raised plasma 1,25-(OH)2D in normal mice, but lowered it in Hyp mice to nondetectable levels. There was no significant effect of the low P diet on plasma levels of 25OHD. We conclude that Hyp mice have a defective control system for plasma levels of 1,25-(OH)2D that does not respond to a low P stimulus with elevated plasma levels of the hormone.

Animals↗
PubMed1981

Effect of 1,25-dihydroxyvitamin D3 on phosphate homeostasis in the X-linked hypophosphatemic (Hyp) mouse.

We studied the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on homeostasis of inorganic phosphate (Pi) in murine hypophosphatemia (Hyp), a homologue of X-linked hypophosphatemia (XLH) in man. Normal mice given 1,25-(OH)2D3 (83 pg/g.d) by continuous subcut, infusion x 10 d) had a significant rise in plasma calcium (Ca) (p less than 0.001), plasma Pi (p less than 0.025) and fractional Ca excretion (p less than 0.001), without change in fractional Pi excretion or Na+-stimulated Pi transport in purified renal brush-border membrane vesicles (BBMV). Hyp littermates did not respond to this dose of 1,25-(OH)2D3. At 415 pg/g.d, Hyp mice had increased plasma Ca (p less than 0.001), fractional Ca excretion (p less than 0.001), and plasma Pi (p less than 0.001) but no change in either fractional Pi excretion or Na+-stimulated Pi transport in BBMV. At this dose, 1,25-(OH)2D3 also stimulated Pi transport by everted sacs of Hyp small intestine (p less than 0.001). No deficiency of Pi transport was found in untreated Hyp intestine. We conclude that 1,25-(OH)2D3 improves Pi homeostasis in the Hyp phenotype by its effect on intestine; the defect in renal Pi reabsorption remains unchanged.

Animals↗
PubMed1982

X-linked hypophosphatemic mice are not hypersensitive to parathyroid hormone.

One of the hypotheses attempting to explain the etiology of the human disease X-linked hypophosphatemia (XLH) posits renal hypersensitivity to parathyroid hormone (PTH). These studies were designed to test this hypothesis in vivo, using the hemizygous hypophosphatemic (Hyp/Y) mouse as an animal model for XLH. Vehicle or 1.0 U bovine PTH (bPTH)/g BW sc was given to intact normal or Hyp mice. Two hours later a small but significant hypercalcemia was observed in both genotypes. Only normal mice remained hypercalcemic 5 h after injection. Intact normal mice, but not Hyp mice, displayed a significant bPTH-induced hypophosphatemia. Administration of bPTH caused a significant increase in both fractional excretion of phosphate (FE-P) and urinary cAMP (UcAMP) 2 h after injection. However, there was no significant differences in the magnitude of response between genotypes. In a different experiment hPTH dose-response curves (0, 0.04, 0.2, and 1.0 U bPTH/g BW sc) were constructed in normal and Hyp mice 18 h after thyroparathyroidectomy (TPTX). bPTH caused a significant hypercalcemia and hypophosphatemia in TPTX normal mice at all doses 2 h after injection. But only the highest dose of hormone caused a significant hypercalcemia in TPTX Hyp mice, and no dose caused a significant decrease in plasma P. In both genotypes a dose-dependent increase in FE-P and UcAMP was observed 2 h after bPTH administration. As with intact mice, there was no indication of a hypersensitive or exaggerated renal response in TPTX Hyp mice. In summary, results from these in vivo experiments indicate that the kidneys of Hyp mice are not hypersensitive to exogenous bPTH. Furthermore, TPTX Hyp mice appeared to exhibit "skeletal resistance" to exogenous PTH, as do osteomalacic dogs and humans. We conclude that renal hypersensitivity to PTH does not play a role in the etiology of XLH in Hyp mice.

Animals↗