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PubMed1982

Increased plasma 1,25-dihydroxyvitamin D after low calcium challenge in X-linked hypophosphatemic mice.

Hyp mice are a model for human X-linked hypophosphatemic (vitamin D-resistant) rickets. We have reported reduced plasma 25-hydroxyvitamin D (25OHD) and normal plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels and (2) failure of low phosphate diets to increase plasma 1,25-(OH)2D in Hyp mice. In this study, we tested the other principal regulatory system of plasma 1,25-(OH)2D by challenging with a low calcium diet. Normal and Hy p mice were fed a control or a low calcium diet for 3 or 7 days. Both normal and Hyp mice showed unchanged plasma phosphate levels and slightly but significantly reduced plasma calcium levels on the low calcium diet. The Hyp mice had significantly elevated plasma parathyroid hormone levels while on the low calcium diet. Plasma 25OHD and 1,25-(OH)2D were measured in the same 4-ml plasma sample by modifications of the Eisman method for 1,25-(OH)2D and the competitive binding assay of Haddad for 25OHD. Each sample was the pooled plasma of 10-14 mice at 13 weeks of age. On the control diet, plasma 1,25-(OH)2D levels were not significantly different in Hyp and normal mice. Plasma 1,25-(OH)2D was elevated in both genotypes on the low calcium diet, but the level in Hyp animals was significantly (P less than 0.05) higher than the level in normal mice. Plasma 25OHD was lower in Hyp than normal and was unaffected by the low calcium diet in either genotype. In summary, whereas Hyp mice do not respond to low phosphate challenge with elevated plasma 1,25-(OH)2D levels, they do respond to low calcium challenge.

Animals↗

PubMed1982

I alpha, 25-Dihydroxyvitamin D3 receptor in the X-linked hypophosphatemic mouse.

We have attempted to determine if the resistance of the X-linked hypophosphatemic mouse to the actions of 1,25(OH)2D3 is due to abnormal cytosolic receptors for this hormone. Cytoplasmic 1,25-dihydroxy-vitamin D3 [1,25(OH)3D3] receptors were demonstrated in hypophosphatemic (HYP) mouse tissues including intestine, kidney and testis. Cytosol preparations from 14 murine tissues were prepared using hypertonic buffer and incubated for three hours at 0 C with 1,25(OH)2 [23,24(n)-(-3)H]D3 ([3H]-1,25(OH)2D3). The results of studies using 5-20% sucrose density gradients revealed th at cytosol preparations from intestine, kidney and testis exhibited a 3.2 S peak which ws specific for 1,25(OH)2D3. Scatchard analysis of intestinal, renal and testicular cytosol preparations of Hyp mice revealed a single class of noninteracting binding sites with a range of equilibrium dissociation constants (KD) of 0.9-3.5 X 10(-10) M, and a range of specific binding sites of 15-317 fmol/mg protein. There were no significant differences in values of KD, and numbers of specific binding sites among Hyp and control mice. We conclude the reported resistance of Hyp mice to vitamin D is not due to abnormal 1,24(OH)2D3 receptor in Hyp mouse.

Animals↗

PubMed1982

Secondary hyperparathyroidism in X-linked hypophosphatemic mice.

Plasma parathyroid hormone (PTH) was measured in adult, age-matched, intact normal mice and Hyp male mice (n = 11/genotype). Hyp mice are an animal model for the human disease X-linked hypophosphatemia. A RIA was used which detects intact and carboxyl-terminal fragments of PTH. Hyp mice were found to have significantly higher plasma PTH levels (0.21 +/- 0.03 ng bovine PTH eq/ml) than normal mice (0.04 +/- 0.03 ng/ml; P less than 0.01). This hyperparathyroidism in the slightly hypocalcemic, osteomalacic Hyp mice may be the result of skeletal resistance to endogenous PTH and may contribute to their characteristically elevated renal excretion of phosphate and urinary cAMP

Animals↗

PubMed1982

Healing of bone lesions with 1,25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse.

The X-linked hypophosphatemic (Hyp) mouse presents with biochemical and skeletal abnormalities similar to those of human vitamin D-resistant rickets and hence is considered as a model of the human disease. In an attempt to correct osteomalacia, young (21-day-old) mutant male mice were infused continuously for 4 weeks with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3; 0.05--0.25 microgram/kg . day]. Mineral and skeletal changes were assessed by serum, urinary, and bone ash concentrations of calcium, phosphorus, and magnesium and by histomorphometric analysis of bone formation measured on histological sections of tetracycline dual labeled undecalcified caudal vertebrae. Treatment with 1,25-(OH)2D3 produced a dose-dependent elevation of serum phosphorous that could be assigned to increased intestinal phosphate absorption. Concomitantly, epiphyseal, endosteal, and periosteal bone mineralization were improved in correlation with both the dosage of 1,25-(OH)2D3 and the serum phosphorus level. Normalization of serum calcium and phosphorus but not of urinary phosphate excretion were achieved together with complete healing of bone mineralization when the highest doses of 1,25-(OH)2D3 (0.175--0.35 microgram/kg . day) were given. The data show that rickets and osteomalacia, which characterize the young Hyp mouse, can be healed by 1,25-(OH)2D3 in doses high enough to normalize serum mineral concentrations. Unlike the renal phosphate leak, the phenotypic expression of the Hyp gene pertaining to bone mineralization is then corrected by 1,25-(OH)2D3 supplementation.

Animals↗

PubMed1983

Abnormal 24-hydroxylation of 25-hydroxyvitamin D in the X-linked hypophosphatemic mouse.

The effect of extracellular phosphate on the control of 25-hydroxyvitamin D3 24-hydroxylase was studied in normal mice and littermates with X-linked hypophosphatemic rickets (Hyp). 24-Hydroxylase activity and plasma concentrations of 24,25-dihydroxyvitamin D3 were significantly higher in Hyp mice than in normal mice when both groups were fed a normal diet containing 1.22% calcium (Ca) and 0.8% phosphorus (Pi). The differential in 24-hydroxylase activity was exaggerated when serum phosphate was reduced in normal mice by means of a low Pi diet or increased in Hyp mice by means of a high Pi diet. Differences in 24-hydroxylase activity between the two groups of mice were also demonstrated in the presence of varying Pi concentrations in vitro. Thus, in both Hyp and normal mice, 24-hydroxylase activity is influenced in a qualitatively similar manner by serum Pi. Plasma concentrations of 1,25-dihydroxyvitamin D3 were the same in normal and Hyp mice. The data are consistent with the hypothesis that control the renal metabolism of 25-hydroxyvitamin D3 in Hyp mice is reset such tht 24-hydroxylase activity is inappropriate high for the prevailing serum phosphate over a wide range of concentrations.

24,25-Dihydroxyvitamin D 3↗

PubMed1983

Abnormal renal mitochondrial 25-hydroxyvitamin D3-1-hydroxylase activity in the vitamin D and calcium deficient X-linked Hyp mouse.

Despite severe hypophosphatemia, plasma levels of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) are not significantly elevated in the Hyp mouse, a murine homologue of X-linked hypophosphatemia in man. To examine the effect of the Hyp mutation on vitamin D hormone biosynthesis, the metabolism of 25-hydroxyvitamin D3 (25-OH-D3) by isolated renal mitochondria was studied. The ability of a vitamin D deficient, low calcium diet to stimulate renal mitochondrial 25-hydroxyvitamin D3-1-hydroxylase activity (1-OHase) in normal mice (n = 22) and Hyp littermates (n = 20) was examined. Both genotypes responded to the diet with an increase in 1-OHase activity and a decrease in 25-hydroxyvitamin D3-24-hydroxylase activity (24-OHase). The increase in 1-OHase activity, however, was significantly lower in Hyp mice (8-fold) than in normal littermates (13-fold, P less than 0.001). In spite of depressed 1-OHase in the mutant strain, enzyme activity was significantly correlated with serum calcium concentration in both normal and Hyp mice. The present results provide direct evidence for an abnormal 1-OHase response in renal mitochondria of Hyp mouse.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1984

Abnormal regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase activity by calcium and calcitonin in renal cortex from hypophosphatemic (Hyp) mice.

25-Hydroxyvitamin D3-1 alpha-hydroxylase activity was assayed in primary serum-free monolayer tissue culture of renal cortical cells from hypophosphatemic (Hyp) mice and normal litter mates. Morphological and growth characteristics of cells from the two genotypes were indistinguishable. Basal enzyme activity was not significantly different in either type of cell over a wide range of substrate concentration. The enzyme from both genotypes was stimulated by PTH and suppressed by increased phosphate concentration in the culture medium. Whereas 1 alpha-hydroxylase activity in cells from normal mice was increased in low calcium medium and suppressed in high calcium medium, the enzyme in cells from Hyp mice was not altered by similar changes in the medium calcium concentration. Salmon calcitonin caused a significant increase in 1 alpha-hydroxylase in cells from normal mice, but did not stimulate enzyme activity in cells from Hyp mice. These studies indicate that control of 1 alpha-hydroxylase activity is abnormal in renal cortical cells from Hyp mice. Impaired control of this enzyme could result in the inappropriately low circulating concentrations of 1,25-dihydroxyvitamin D3 that have been observed in humans with hypophosphatemic rickets and in the relatively low activity of 1 alpha-hydroxylase in renal cortical homogenates of Hyp mice compared to that in normal mice on a low phosphate diet.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1984

Investigation of the mechanism for abnormal renal 25-hydroxyvitamin D3-1-hydroxylase activity in the X-linked Hyp mouse.

Renal mitochondria from mutant hypophosphatemic male mice (Hyp/Y) fed a vitamin D-deficient, low calcium diet synthesize significantly less 1,25-dihydroxyvitamin D3 than mitochondria from normal male (+/Y) littermates on the same diet. Kinetic studies reveal that maximum velocity (Vmax) for 25-hydroxyvitamin D3-1-hydroxylase (1-hydroxylase) is lower in Hyp/Y relative to +/Y mice (0.21 +/- 0.02 vs. 1.06 +/- 0.12 pmol/mg protein X min) whereas the apparent Michaelis-Menten constant (Km) for the reaction is not different in both genotypes (0.55 +/- 0.05 vs. 0.50 +/- 0.08 microM). The presence of an inhibitor for 1-hydroxylase activity in renal mitochondria of Hyp/Y mice was ruled out by estimating enzyme activity in mixtures of renal mitochondria from +/Y and Hyp/Y mice. Phosphate in the incubation medium stimulated 1-hydroxylase activity in +/Y mitochondria. In Hyp/Y mice, the stimulation achieved was smaller in magnitude and the added phosphate did not restore mutant 1-hydroxylase activity to normal. The vitamin D-deficient, low calcium diet led to a significant and comparable increase in serum PTH and urinary excretion of cAMP in +/Y and Hyp/Y, suggesting that the mutant strain had an appropriate PTH response to the diet-induced fall in serum calcium. Furthermore, the fractional excretion index of phosphate which is significantly greater in Hyp/Y than +/Y mice fed the control diet increased 3-fold in both genotypes fed the vitamin D-deficient, low calcium diet. These results suggest that the abnormal renal 1-hydroxylase response in Hyp mice is not the result of generalized renal resistance to PTH in the mutant strain and suggest that the defect in Hyp/Y mice may reside at a regulatory step subsequent to cAMP production.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1984

Low levels of intestinal vitamin D-dependent calcium-binding protein in juvenile X-linked hypophosphatemic mice.

Hyp mice are a model for human X-linked hypophosphatemia, the most common form of vitamin D-resistant rickets. The developmental appearance of intestinal vitamin D-dependent calcium-binding protein (CaBP) and alkaline phosphatase was studied in Hyp mice and normal mice from the perinatal period to adulthood. Both intestinal proteins were increased in the duodenum during weeks 2 and 3 of age, with values rising 10-fold or more above values measured in intestines of 1-week-old mice. During this developmental period and at most other ages, Hyp mice had levels of alkaline phosphatase and total intestinal protein comparable to those in control mice. On the other hand, the concentration of intestinal CaBP was decreased in juvenile Hyp mice during the weaning period at 2-3 weeks of age (35-65% of normal) and further depressed in the rapid growth phase at 4-6 weeks of age (15-45% of normal). During adulthood (7-35 weeks of age) Hyp mice maintained a CaBP concentration that averaged 71% of the level of control mice. These maturational defects in the Hyp intestine may play a contributory role in the bone disease in young Hyp mice.

Alkaline Phosphatase↗

PubMed1984

A role for the intestine in the bone disease of juvenile X-linked hypophosphatemic mice: malabsorption of calcium and reduced skeletal mineralization.

Low duodenal vitamin D-dependent calcium-binding protein has been reported in juvenile Hyp mice. Levels of this protein improved in adult Hyp mice. This led to the search for possible abnormal intestinal calcium absorption in juvenile Hyp mice and for evidence that calcium malabsorption, if present, would exacerbate the bone disease. A balance study was performed in 10 sets of normal and Hyp male mice at 5 and 12 weeks of age. Twelve-week-old Hyp mice had balances (24-h intake minus excretion) of Ca, P, Mg, Na, and K that were not significantly different from those of 12-week-old normal mice. However, 5-week-old Hyp mice had a significantly lower balance of Ca with higher fecal Ca and lower urinary Ca. No balance was also lower due to higher fecal Na. The balances of P, Mg, and K were not significantly affected in young Hyp mice. Growth and mineralization of the femur were compared in normal and heterozygous female Hyp mice from 3.5-46 weeks of age. The femora of Hyp mice gained ash weight at a rate comparable to that for normal mice, except for a lag between 3.5 and 7 weeks. There was life-long hypophosphatemia and elevated plasma alkaline phosphatase. It was concluded that the period of low levels of duodenal vitamin D-dependent calcium-binding protein was associated with low intestinal absorption and low skeletal mineralization. This dysfunction of the intestine in juvenile, rapidly growing Hyp mice may exacerbate the bone disease.

Alkaline Phosphatase↗

PubMed1985

Thyroid hormones increase renal brush border membrane transport of phosphate in X-linked hypophosphatemic (Hyp) mice.

Hyp mice, the murine homolog of human X-linked hypophosphatemia (XLH), are characterized in part by elevated renal loss of phosphate (Pi) and hypophosphatemia. The lesion responsible for this syndrome is believed to be defective Na+ gradient-dependent phosphate transport across renal brush border membranes (BBM). It has been demonstrated that thyroid hormones can stimulate Pi uptake by rat BBM vesicles (BBMV). The purpose of this current study was to determine whether thyroid hormones could increase renal BBMV transport of Pi and improve the renal conservation of Pi in Hyp mice. Hyp mice were treated with either vehicle (controls) or T4 (0.2 mg/100 g BW, ip, once daily) for 6 days. At the end of the treatment period, the uptake of 32Pi (at 30 sec), in the presence of a Na+ gradient (Na+o greater than Na+i) by BBMV prepared from renal cortex of T4-treated Hyp mice, was significantly increased (+25%) compared to that in vehicle-treated Hyp controls. The uptake of L-[3H]proline (at 10 sec) by the same BBMV preparation was unchanged. T4-treated Hyp mice displayed a significant decrease in urinary Pi excretion (-31%), and a restoration of plasma Pi levels (+52%) to the normal range. Plasma calcium, creatinine, and magnesium as well as urinary excretion of cAMP did not change with T4 treatment. Another group of Hyp mice was given T3 (0.2 mg/100 g BW, ip) at three 12-h intervals. After 36 h, the rate of 32Pi uptake by renal BBM was significantly increased (+40%). Plasma Pi also increased (+26%). Our findings indicate that parenteral administration of thyroid hormones specifically increased (compared to transport of L-proline) the capacity of Na+ gradient-dependent renal BBM Pi uptake in Hyp mice, decreased renal Pi excretion, and increased plasma Pi. These results suggest that treatment with T4 or T3 can enhance the defective proximal tubular reabsorption of Pi and improve renal Pi retention in murine X-linked hypophosphatemia.

Animals↗

PubMed1985

Protein kinase activity and protein kinase inhibitor in mouse kidney: effect of the X-linked Hyp mutation and vitamin D status.

cAMP-dependent protein kinase, Ca+2- and phospholipid-dependent protein kinase, and protein kinase inhibitor activity were examined in renal homogenates and 20,000 X g supernatant fractions of normal and Hyp mice. In both genotypes, 70% of total renal cAMP-dependent protein kinase activity was recovered in the soluble fraction in which the activity ratio (without cAMP to with cAMP) of the enzyme was 0.35. The requirement for cAMP was not different for protein kinase of normal and mutant littermates, with an apparent Km for cAMP of 0.05 microM in both genotypes. Furthermore, vitamin D and calcium deficiencies did not significantly affect cAMP-dependent protein kinase activity in normal and Hyp mouse kidney. The concentration of the heat-stable protein kinase inhibitor protein in the 20,000 X g supernatant fraction was identical in normal and Hyp kidney. Whereas protein kinase inhibitor levels were increased 1.8-fold by vitamin D and calcium deficiencies in normal mice (P less than 0.001), no such increase was detectable in Hyp mice. Ca+2- and phospholipid-dependent-protein kinase (protein kinase C) activity in the 20,000 X g supernatant fraction comprised 50% of the total activity of kidney homogenates of both normal and mutant mice. The initial rate of protein kinase C was increased 1.5-fold in kidney supernatants of Hyp mice (P less than 0.001). In contrast, protein kinase C was not significantly different from normal in supernatant fractions of heart, spleen, and liver prepared from Hyp mice. The present demonstration of abnormally high renal protein kinase C activity in Hyp mice may serve to explain the relationship between the previously reported renal defects in brush border membrane phosphate transport and vitamin D metabolism in the mutant strain and elucidate the nature of the primary defect in the Hyp mouse.

Animals↗

PubMed1985

Decreased nuclear uptake of 1,25-dihydroxyvitamin D3 by duodenal mucosal cells in the X-linked hypophosphatemic mouse.

We have shown that there is a significant decrease in the nuclear uptake of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by duodenal mucosal cells in the X-linked hypophosphatemic (Hyp) mouse. Duodenal mucosal cells prepared from control and Hyp mice were incubated with 1,25(OH)2[26,27-methyl-3H]D3 ([3H]-1,25(OH)2D3) for 30 min. to evaluate the time-course and perform saturation analysis. The results of time-course studies showed that saturation was attained in 30 min., reaching an average nuclear uptake of 10.4 fmol/tube in the control mice and 6.1 fmol/tube in the Hyp mice. The results of Scatchard analyses were as follows: dissociation constant (Kd) 5.71 X 10(-10) M and maximal binding sites 7.31 X 10(4) sites/cell in the control mice, and Kd 2.92 X 10(-10) M and maximal binding sites 4.88 X 10(4) sites/cell in the Hyp mice, the maximal binding sites of the latter showed a significant decrease (P less than 0.05) by Student's t test. In addition, there was no significant difference in the binding of [3H]-1,25(OH)2D3 to its residual cytosol receptors between the control and Hyp mice. On the basis of these data, we speculate that the reported resistance of Hyp mice to vitamin D may be due to decreased nuclear uptake of 1,25(OH)2D3 by their duodenal mucosal cells.

Animals↗

PubMed1986

Increased metabolic rate in X-linked hypophosphatemic mice.

Hyp mice are a model for human X-linked hypophosphatemia, the most common form of vitamin D-resistant rickets. It has previously been observed that Hyp mice have a greater food consumption per gram body weight than do normal mice. This led to the search for some alteration in metabolism in Hyp mice. We found that oxygen consumption was significantly higher in Hyp mice than in normal C57BL/6J mice and this was accompanied by an increased percentage of cardiac output being delivered to organs of heat production (liver and skeletal muscle), to the skin, and to bone and a decreased percentage to the gastrointestinal tract of Hyp mice. The increased oxygen consumption in Hyp mice was not associated with increased plasma free T4 levels and was not affected by alterations in plasma phosphate produced by a low phosphate diet. The cause of the increased oxygen consumption is not known, and the role that this change and reported changes in distribution of cardiac output may play in the development of X-linked hypophosphatemia is also unknown. Study of the cardiovascular and thermoregulatory systems in Hyp mice should help increase understanding of the underlying mechanisms of this disease.

Animals↗

PubMed1986

Effect of the Hyp mutation and diet-induced hyperparathyroidism on renal parathyroid hormone- and forskolin-stimulated adenosine 3',5'-monophosphate production and brush border membrane phosphate transport.

The present study was undertaken to investigate the effect of the Hyp mutation and diet-induced hyperparathyroidism on renal responsiveness to PTH and forskolin and to determine whether the renal brush border membrane phosphate transport defect is expressed in the vitamin D- and calcium-deficient Hyp mouse. Our results indicate that PTH is a potent activator of cAMP synthesis in renal slices obtained from vitamin D-replete normal mice and Hyp littermates. However, in the mutants, the amount of cAMP produced in response to similar concentrations of PTH (0.005-5 U/ml) is 55% of normal (P = 0.0076). PTH-dependent cAMP synthesis is significantly reduced in both normal and Hyp mice fed the vitamin D-deficient low calcium diet, and under these conditions, genotype differences are no longer apparent. In contrast, forskolin-stimulated cAMP production is identical in vitamin D-replete normal and mutant mice. Furthermore, cAMP accumulation in response to forskolin is not decreased by diet-induced hyperparathyroidism in either genotype. Vitamin D and calcium deprivation results in a significant decrease in renal brush border membrane Na+-dependent phosphate transport in both genotypes, and under these conditions, the phosphate transport defect persists in Hyp mice. Finally, vitamin D and calcium deprivation has no effect on renal brush border membrane alkaline phosphatase activity. The present results suggest that the catalytic subunit of adenylate cyclase is intact in the mutant strain and that the blunted renal response to PTH in vitamin D-replete Hyp mice as well as in vitamin D- and calcium-deficient mice may be due to uncoupling of the PTH-receptor-adenylate cyclase system. The data also suggest that the expression of the renal phosphate transport defect in Hyp mice is independent of PTH status and alkaline phosphatase activity.

Alkaline Phosphatase↗

PubMed1987

Vitamin D-dependent calcium binding proteins in the kidney and intestine of the X-linked hypophosphatemic mouse: changes with age and responses to 1,25-dihydroxycholecalciferol.

We have previously observed decreased intestinal 9 kilodalton (kd) vitamin D-dependent calcium binding protein (CaBP) and decreased calcium absorption in juvenile X-linked hypophosphatemic (Hyp) mice. The present studies were undertaken to examine whether the kidney CaBPs (9 kd and 28 kd) are also affected in young Hyp mice and to investigate the ability of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] to increase CaBP in the intestine and kidney. The 28 kd CaBP and the 9 kd CaBP were measured in the kidneys and the 9 kd CaBP in the intestines of normal and Hyp mice from 1 week to 40 weeks of age. At all times between 3 and 6 weeks, intestinal CaBP in Hyp mice was decreased by more than 50% (P less than 0.005-0.001) and no significant decrease was present in the adult Hyp mice (12 and 40 weeks of age). By contrast, both kidney CaBPs were decreased only slightly in young Hyp mice. Between 1 and 6 weeks of age, the 9 kd CaBP in Hyp mice was 82% +/- 4% of control (P less than 0.001) and the 28 kd protein was 89% +/- 3% of control (P less than 0.001). Minipumps containing 1,25-(OH)2D3 or vehicle were implanted in 4-week and 13-week-old Hyp mice for 3 days to provide a dose of 0.12 micrograms/kg mouse X day. The 9 kd CaBP was increased approximately 3-fold (P less than 0.001) by 1,25-(OH)2D3 in the intestines of Hyp mice at both ages. The 9 kd kidney CaBP in Hyp mice also was increased by 1,25-(OH)2D3 treatment at both ages, but only by 33-52%. The 28 kd CaBP in the kidney was not affected by 1,25-(OH)2D3 treatment of Hyp mice at either age. We conclude that (9 kd and 28 kd) CaBPs levels in both intestine and kidney are decreased in juvenile Hyp mice although to much different degrees. The administration of 1,25-(OH)2D3 to Hyp mice increases the 9 kd CaBP in both intestine and kidneys, whereas the renal 28 kd CaBP is unaffected.

Aging↗

PubMed1988

Effects of the administration of phosphate on nuclear 1,25-dihydroxyvitamin D3 uptake by duodenal mucosal cells of Hyp mice.

Effects of the administration of phosphate on nuclear 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] uptake by duodenal mucosal cells of Hyp mice were investigated. In Hyp mice fed a high phosphate diet (1.1% Ca and 2.0% phosphate) for 2 weeks, maximal nuclear 1,25-(OH)2D3 binding by duodenal mucosal cells is significantly increased from 5.01 +/- 0.49 x 10(3) to 8.23 +/- 1.10 x 10(3) sites/cell (P less than 0.05). No significant change was observed in normal mice fed the same diet. The serum phosphate concentration of Hyp mice increased significantly (P less than 0.01), whereas no significant change was found in normal mice. On this regimen, serum calcium, urinary cAMP to creatinine ratio, and cytosolic 1,25-(OH)2D3 receptor number in Hyp mice were not changed significantly. On the basis of these data, we speculate that the recovery of serum phosphate in Hyp mice fed a high phosphate diet affects the recovery of nuclear 1,25-(OH)2D3 uptake by duodenal mucosal cells. The mechanism for this recovery is not related to either the secondary hyperparathyroidism or the change in cytosolic 1,25-(OH)2D3 receptor content but, rather, to increased binding of 1,25-(OH)2D3-receptor complex to nuclei. Hypophosphatemia, therefore, appears to play a role in the vitamin D resistance in Hyp mice.

Animals↗

PubMed1988

Defective bone formation by transplanted Hyp mouse bone cells into normal mice.

The hypophosphatemic (Hyp) mouse is a model for human X-linked hypophosphatemia (XLH). To test the hypothesis of an abnormal osteoblast function in XLH, periostea and osteoblasts isolated from normal and Hyp mice were transplanted im into normal and mutant mice. The thickness of the osteoid seams at the periphery of the bone nodules and the osteoid volume were measured in transplants as an index of bone formation. Impaired mineralization was evidenced in transplants of Hyp cells into Hyp mice by excessive osteoid thickness and volume compared with transplants of normal cells into normal mice. When normal cells were transplanted into mutant mice, the osteoid thickness and volume were markedly increased, demonstrating that the extracellular environment is critical for bone formation. In contrast, when Hyp cells were transplanted into normal mice, reduction, but not normalization, of the osteoid thickness and volume was observed. This abnormal bone formation supports the hypothesis of an osteoblast defect in the Hyp mouse.

Animals↗