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PubMed1989

Abnormal adenosine 3'.5'-monophosphate stimulation of renal 1,25-dihydroxyvitamin D production in hyp mice: evidence that 25-hydroxyvitamin D-1 alpha-hydroxylase dysfunction results from aberrant intracellular function.

Previously we have established that abnormal regulation of renal 25-hydroxyvitamin D (25OHD)-1 alpha-hydroxylase in Hyp mice involves the PTH-adenylate cyclase component of enzyme activation. However, it remains unknown if the muted effects of PTH result from 1) abnormal second messenger production or 2) an intracellular defect limiting enzyme activation. To distinguish between these possibilities, we compared cAMP stimulation of renal 25OHD-1 alpha-hydroxylase in normal, phosphate-depleted normal, and Hyp mice. Administration of N6-monobutyryl cAMP iv (200 mg/kg/day) increased enzyme activity in normal (4.1 +/- 1.7 vs. 40.7 +/- 7.0 fmol/mg kidney.min) and phosphate-depleted mice (13.3 +/- 1.8 vs. 78.2 +/- 10.4) to a level significantly greater than that achieved in Hyp mice (7.4 +/- 1.1 vs. 22.7 +/- 3.6). Moreover, similar to our observations after PTH stimulation, the apparent abnormal cAMP effect did not result from an altered time course of enzyme activation or a rightward shift in the dose response. Collectively, these data indicate that abnormal regulation of 1,25-dihydroxyvitamin D production in Hyp mice results from aberrant intracellular regulation of 25OHD-1 alpha-hydroxylase, a defect probably related to deranged phosphate transport in the renal tubule.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1992

Altered proximal tubule glucose metabolism in X-linked hypophosphatemic mice.

In the present study we examined renal proximal tubule glucose metabolism in the X-linked hypophosphatemic (Hyp/Y) mouse. Compared to those in its normal (+/Y) littermate, Hyp/Y mouse proximal tubules showed a higher rate of glucose production when using glutamine or alpha-ketoglutarate as a substrate. The glucose production rate was not, however, different when using malate or fructose as the substrate. PTH stimulated glucose production in +/Y, but not Hyp/Y, mouse proximal tubules. The PTH resistance in Hyp/Y mouse involves steps at and post-cAMP formation, because in Hyp/Y mouse proximal tubules PTH effects a lesser stimulation of cAMP generation, and addition of 8-bromo-cAMP failed to increase the glucose production rate. The rate of glucose utilization as a whole was not different in the two groups, but the rate of glucose metabolized through the pentose cycle (PC) pathway was markedly lower in Hyp/Y mouse proximal tubules. The lower PC activity in Hyp/Y mouse proximal tubules did not result from a defect of PC enzymes, because both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase enzyme activities were intact, and phenazine methosulfate was able to stimulate PC activity. The higher rate of glucose production and the lower rate of PC activities persisted in the in vitro cultured Hyp/Y mouse proximal tubular cells. These results suggest that the altered glucose metabolism in the Hyp/Y mouse proximal tubule is not maintained by external influences and may be an abnormality intrinsic to these cells.

Animals↗
PubMed1992

Renal phosphate transport and vitamin D metabolism in X-linked hypophosphatemic Gy mice: responses to phosphate deprivation.

Two closely linked, nonallelic genes, Gy and Hyp, result in X-linked hypophosphatemia in mice. The present studies in Gy mice were undertaken to determine whether renal brush-border membrane Na(+)-phosphate cotransport kinetics and adaptive responses of renal phosphate transport and vitamin D metabolism to phosphate deprivation are comparable in the two mutant strains. Transport studies in purified brush-border membrane vesicles over a phosphate concentration range of 10-500 microM demonstrated that the apparent maximum velocity of the high affinity transport system is significantly decreased in Gy mice (420 +/- 110 vs. 710 +/- 100 pmol/mg protein.6 sec, Gy vs. normal; mean +/- SE; P less than 0.05), whereas the affinity of the cotransporter for phosphate is unchanged (apparent Km, 25 +/- 3 vs. 27 +/- 2 microM; NS). Feeding a low phosphate diet results in a significant fall in plasma phosphate and an increase in brush-border membrane Na(+)-phosphate cotransport in both normal (568 +/- 40 to 1416 +/- 139 pmol/mg protein.6 sec; P less than 0.01) and Gy mice (407 +/- 27 to 1236 +/- 132 pmol/mg protein.6 sec; P less than 0.01). While the low phosphate diet elicited a rise in plasma 1,25-dihydroxyvitamin D in normal mice (51 +/- 12 to 158 +/- 12 pM; P less than 0.01), a fall in plasma hormone levels was evident in phosphate-deprived Gy mice (90 +/- 22 to 23 +/- 11 pM; P less than 0.01). Phosphate deprivation decreased 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase), the first enzyme in the renal vitamin D catabolic pathway, in normal mice (117 +/- 21 to 69 +/- 8 fmol/mg protein.min), but increased enzyme activity in Gy mice (172 +/- 14 to 240 +/- 18 fmol/mg protein.min; P less than 0.05). Moreover, under both dietary conditions, 24-hydroxylase activity was significantly elevated in Gy mice. The present results demonstrate that hypophosphatemia in Gy mice can be attributed to a decrease in the maximum velocity of the high affinity Na(+)-phosphate cotransport process in renal brush-border membranes. Our results also show that while renal brush-border membrane phosphate transport is appropriately modulated by phosphate in Gy mice, phosphate regulation of vitamin D metabolism is apparently impaired in the mutant strain. The present findings provide evidence for phenotypic similarities between murine Gy and Hyp mutations.

Animals↗
PubMed2001

Osteomalacia in hyp mice is associated with abnormal phex expression and with altered bone matrix protein expression and deposition.

To explore how the loss of Phex function contributes to the pathogenesis of osteomalacia, we examined the abnormalities of mineralization, Phex, and bone matrix protein expression occurring in Hyp mice in vivo and in ex vivo bone marrow cell cultures. The results in vivo show that mineralization was decreased significantly in Hyp mouse bone. Phex protein was identifiable in osteoblasts and osteocytes in wild-type mice, but not in Hyp mice. In Hyp mice, osteocalcin, bone sialoprotein, and vitronectin expression were down-regulated, whereas biglycan and fibrillin-1 expression were up-regulated in osteocytes and bone matrix relative to those in their wild-type counterparts. Parallel studies ex vivo demonstrated that cells derived from 18-day Hyp mouse bone marrow cell cultures had a 3'-Phex deletion, no Phex protein expression, decreased alkaline phosphatase activity, collagen deposition, and calcium accumulation, and reduced osteocalcin, bone sialoprotein, and vitronectin at both the protein and messenger RNA levels. Furthermore conditioned medium from Hyp mouse bone marrow cultures could induce analogous defects in bone marrow cell cultures of wild-type cells. These novel findings indicate that there is an intrinsic osteogenic cell differentiation defect in addition to the known hypomineralization of bone in Hyp mice, which may be inducible by an autocrine/paracrine secreted factor. These results suggest that alterations in the Phex gene may control bone matrix mineralization indirectly by regulating the synthesis and deposition of bone matrix proteins.

Animals↗
PubMed2002

Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.

FGF-23 is involved in the pathogenesis of two similar hypophosphatemic diseases, autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced osteomalacia (TIO). We have shown that the overproduction of FGF-23 by tumors causes TIO. In contrast, ADHR derives from missense mutations in FGF-23 gene. However, it has been unclear how those mutations affect phosphate metabolism. Therefore, we produced mutant as well as wild-type FGF-23 proteins and examined their biological activity. Western blot analysis using site-specific antibodies showed that wild-type FGF-23 secreted into conditioned media was partially cleaved between Arg(179) and Ser(180). In addition, further processing of the cleaved N-terminal portion was observed. In constrast, mutant FGF-23 proteins found in ADHR were resistant to the cleavage. In order to clarify which molecule has the biological activity to induce hypophosphatemia, we separated full-length protein, the N-terminal and C-terminal fragments of wild-type FGF-23. When the activity of each fraction was examined in vivo, only the full-length FGF-23 decreased serum phosphate. Mutant FGF-23 protein that was resistant to the cleavage also retained the activity to induce hypophosphatemia. The extent of hypophosphatemia induced by the single administration of either wild-type or the mutant full-length FGF-23 protein was similar. In addition, implantation of CHO cells expressing the mutant FGF-23 protein caused hypophosphatemia and the decrease of bone mineral content. We conclude that ADHR is caused by hypophosphatemic action of mutant full-length FGF-23 proteins that are resistant to the cleavage between Arg(179) and Ser(180).

Amino Acid Sequence↗
PubMed2002

Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia.

Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25-dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and tumor-induced osteomalacia. Although the involvement of a newly identified factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical evidence indicating the role of FGF-23 has been lacking. We have previously shown that FGF-23 is cleaved between Arg(179) and Ser(180), and this processing abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore, sandwich ELISA for biologically active intact human FGF-23 was developed using two kinds of monoclonal antibodies that requires the simultaneous presence of both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23 in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast, those in a patient with TIO were over 200 ng/L. After the resection of the responsible tumor, the elevated FGF-23 level returned to normal level within 1 h. The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate, and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23. In addition, the elevated serum FGF-23 levels were demonstrated in most patients with XLH. It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.

Adult↗
PubMed2003

Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets.

X-Linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia, rickets, and impaired growth. Despite oral phosphate and 1,25-dihydroxyvitamin D(3) treatment, many patients have suboptimal growth and bone healing. The aim of this study was to assess whether age at treatment onset impacts the outcome. Growth data, biochemistry, and radiographs of 19 well-controlled patients with XLH were analyzed retrospectively. Patients were divided into two groups based on the age at treatment onset (group 1, <1.0 yr; group 2, >or=1.0 yr). The median height z-score was higher in group 1 (n = 8) than in group 2 (n = 11) at treatment onset [-0.4 SD score (SDS) vs. -1.7 SDS; P = 0.001], at the end of the first treatment year (-0.7 SDS vs. -1.8 SDS; P = 0.009), throughout childhood (P > 0.05) and until predicted adult height (-0.2 SDS vs. -1.2 SDS; P = 0.06). The degree of hypophosphatemia was similar in both groups, but serum alkaline phosphatase remained higher in group 2 throughout childhood. Radiographic signs of rickets were more marked in group 2, but even patients with early treatment developed significant skeletal changes of rickets. These data suggest that treatment commenced in early infancy results in improved outcome in patients with XLH, but does not completely normalize skeletal development.

Age of Onset↗
PubMed1975

Total body retention of orally administered 47-calcium in primary hyperparathyroidism.

Using a whole body radiation detector, we have measured the total body retention of 47-Ca 7 days after oral administration of the isotope to patients with various disorders of calcium metabolism. The percent retention of 47-Ca given with 90 mg of unlabeled (carrier) calcium varied with the calcium metabolic status as follows: normals (n equals 14), 33-43 percent (mean 38); primary hyperparathyroidism (n equals 28), 32-74 percent (mean 52); idiopathic hypercalciuria (n equals 9), 34-49 percent (mean 42); and hypercalcemia of other etiology (n equals 3), 23-26 percent (mean 25). Almost half (13/28) of those with hyperparathyroidism showed a retention above 55 percent, distinguishing them from subjects with idiopathic hypercalciuria. Retention of 47-Ca correlated poorly with clinical measures of severity of hyperparathyroidism. When isotope was diluted with a smaller amount of carrier calcium (20 mg), retention was increaseed in normals (n equals 5) to 46-54 percent (mean 50) and in hyperparathyroidism (n equals 5) to 64-87 percent (mean 73). After surgical cure of hyperparathyroidism retention of isotope returned toward normal in 5 of 7 subjects. Whole body retention of orally administered 47-Ca may prove useful in detecting hyperparathyroidism in subjects with mild hypercalcemia or hypercalciuria.

Administration, Oral↗
PubMed1978

Effect of oral glucose ingestion on renal phosphate reabsorption and clearance in vitamin D-resistant rickets.

The effect or oral glucose ingestion on renal phosphate reabsorption was studied in 13 patients with the inherited form of vitamin D-resistant rickets (VDRR) and 5 normal subjects. In contrast to the normal subjects, glycosuria developed in six VDRR patients after glucose ingestion and resulted in a further 43% decrease in renal phosphate reabsorption. This was accompanied by a 33% increase in phosphate clearance. This was not attended by differences in fasting glucose or phosphorus levels between groups, or in their respective values 1 h after glucose ingestion. Baseline renal phosphate reabsorption was less and baseline phosphate clearance was greater in those VDRR subjects who developed glycosuria. The accumulated data suggest that excessive glucose ingestion by some patients with VDRR may add an additional insult to the phosphaturia characteristic of this disorder. This, in turn, would further compromise the response of circulating phosphate to therapeutic attempts at oral phosphate supplementation, thereby reducing the efficacy of oral phosphate therapy on skeletal growth and development in this disorder.

Adolescent↗
PubMed1980

An unusual form of vitamin D-dependent rickets in a child: alopecia and marked end-organ hyposensitivity to biologically active vitamin D.

A 12-yr-old female patient with an unusual form of vitamin D dependency and alopecia is described. She was a product of consanguineous mating and developed signs and symptoms suggesting vitamin D dependency early in life. Neither 150 microgram/day (6 microgram/kg.day) 1 alpha-hydroxyvitamin D3 nor 5 microgram/day (0.2 microgram/kg.day) 1,25-dihydroxyvitamin D3 proved to have an effect on her abnormal serum chemistry. Seven million international units per day (about 2 x 10(5) IU/kg.day) of native vitamin D restored her serum chemistry to normal and brought about marked improvement on skeletal radiographs, when her serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and 24,25-di-hydroxyvitamin D were 4250, 4.8, and 35 ng/ml, respectively. Even with the high serum levels of vitamin D metabolites, her intestinal 47Ca absorption rate remained in the lower normal range and urinary calcium excretion was decidedly low. Association of hypoparathyroidism was ruled out. These results suggest that the patient has extreme and-organ (intestine) hyposensitivity, probably of congenital origin, to the biologically active metabolites of vitamin D.

Alopecia↗
PubMed1981

X-linked hypophosphatemia: effect of calcitriol on renal handling of phosphate, serum phosphate, and bone mineralization.

Eleven patients with the Mendelian phenotype of x-linked hypophosphatemia (XLH) were treated with calcitriol [1,25-(OH)2D3] and phosphate. Ten patients had received prior treatment with ergocalciferol and phosphate. Five subjects were prepubertal and six were postpubertal. Response to calcitriol was measured under nonfasting and overnight fasting protocols. Bone biopsies were obtained before and after treatment. Calcitriol (mean dose, 30 ng/kg. day) 1) raised serum phosphorus uniformly in prepubertal patients but in only two of six postpubertal subjects; 2) did not change the theoretical renal phosphate threshold in the total patient group and thus had no effect on the primary transport defect in XLH; 3) improved trabecular bone mineralization in the total patient group, as determined by bone histomorphometry. The beneficial effect on extracellular phosphorus homeostasis was attributed to improved intestinal absorption of phosphorus; improvement in bone mineralization may reflect an additional effect of 1,25-(OH)2D3 on bone itself in XLH. Mild transient hypercalcemia occurred during 0.6% of 3545 treatment days and was readily controlled by adjusting the dosage of 1,25-(OH)2D3.

Adolescent↗
PubMed1982

Parathyroid hormone effects on serum 1,25-dihydroxyvitamin D levels in patients with X-linked hypophosphatemic rickets: evidence for abnormal 25-hydroxyvitamin D-1-hydroxylase activity.

Patients with X-linked hypophosphatemic rickets (XLH) have normal or marginally low serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels despite manifesting hypophosphatemia and phosphate depletion, which increase 1,25-(OH)2D production in many animal species. These data are consistent with the possibility that regulation of vitamin D metabolism is abnormal in XLH. However, controversy concerning the role of phosphate in the regulation of 25-hydroxyvitamin D-1-hydroxylase activity in man has raised doubt about this proposed defect. The presence of a defect in vitamin D metabolism could be established if hormonal or metabolic factors, other than hypophosphatemia, were unable to stimulate 25-hydroxyvitamin D-1-hydroxylase activity normally in patients with XLH. Thus, we compared the effects of parathyroid hormone infusion on serum 1,25-(OH)2D levels in patients with XLH and normals. In response to iv infusion of parathyroid extract (200 U at 0915 and 1700 h), the serum 1,25-(OH)2D concentration increased 218% above base line (from 34.0 +/- 3.0 to 108.8 +/- 2.5 pg/ml) in normals and only 68% (from 30.6 +/- 3.0 to 48.8 +/- 5.5 pg/ml) in patients with XLH. The disparate response occurred in spite of an equivalent increase in urinary cAMP excretion in the normals (from 3.00 +/- 0.14 to 8.70 +/- 0.25 mumol/g creatinine . 24 h) and XLH patients (from 3.10 +/- 0.39 to 8.30 +/- 1.0 mumol/g creatinine . 24 h) as well as equivalent decreases in the renal tubular maximum for the reabsorption of phosphate per liter glomerular filtrate (1.2 +/- 0.1 and 0.9 +/- 0.2 mg/dl, respectively). These observations support the possibility that regulation of vitamin D metabolism is abnormal in XLH.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1982

Vitamin D resistant rickets with alopecia: cultured skin fibroblasts exhibit defective cytoplasmic receptors and unresponsiveness to 1,25(OH)2D3.

A new case of vitamin D dependent rickets (Type II) with alopecia in a 5 yr old child is reported. Skin fibroblasts were propagated in culture and analyzed for cytoplasmic 1,25(OH)2D3 receptors. The rachitic cells failed to exhibit specific, high-affinity binding sites by either Scatchard analysis or sucrose density gradient. Furthermore, a rise in 24-hydroxylase activity could not be elicited following incubation of the rachitig cells with 1,25(OH)2D3. Fibroblasts from a non-rachitic child examined in parallel experiments demonstrated high affinity binding sites (Kd = 0.1 nM, Nmax = 33 fmol/100 micrograms DNA) and the induction of 24-hydroxylase activity. The molecular basis of the unresponsiveness of the cells from the rachitic child appears to be due to defective or absent 1,25(OH)2D3 receptors.

Alopecia↗
PubMed1983

Rickets and alopecia with resistance to 1,25-dihydroxyvitamin D: two different clinical courses with two different cellular defects.

UNLABELLED: Two unrelated patients, aged 22 months and 31 months, with alopecia and rickets resistant to 1,25-dihydroxyvitamin D (1,25-(OH)2D] (vitamin D-dependency type II) presented with similar biochemical and radiologic features. They were treated with large doses of vitamin D3 derivatives [25-hydroxyvitamin D3 (25-(OH)D3), 1,25-(OH)2D3, and 1 alpha-hydroxyvitamin D3] for 28 months and 6 yr, respectively. In both patients, serum 1,25-(OH)2D levels remained high (approximately 10- to 100-fold normal) during the different therapeutic regimens. Circulating 1,25-(OH)2D and 24,25-dihydroxyvitamin D levels at various stages of the disease suggested in these children disturbances in the regulation of 25-hydroxyvitamin D (25(OH)D) 1 alpha- and 24-hydroxylase systems. In one child, all therapeutic trials were unsuccessful. Studies of her cultured skin fibroblasts showed low capacity (10% normal) for saturable (presumably receptor mediated) nuclear uptake of tritiated 1,25-(OH)2D3; the uptake process of nucleus associated 1,25-(OH)2D3 was normal in apparent affinity for 1,25-(OH)2D3 and in sedimentation velocity of nucleus-associated hormone. In the second child, correction of biochemical abnormalities, healing of rickets, and catch-up growth were obtained during similar therapeutic trials up to the age of 6 yr when a relapse occurred. This relapse has persisted for 2 yr in spite of similar or higher circulating concentrations of 25-(OH)D and 1,25-(OH)2D than those obtained previously when she was responsive to therapy. In her cultured skin fibroblasts, saturable high affinity nuclear uptake of 1,25(OH)2D was unmeasurable. IN CONCLUSION: 1) distinct patterns of clinical response can occur in patients with the syndrome of vitamin D-dependency type II, and can be associated with differing abnormalities in interaction of 1,25-(OH)2D3 with cultured skin fibroblasts; 2) aggravation of the resistance to 1,25-(OH)2D3 may occur during long term therapy in some patients.

24,25-Dihydroxyvitamin D 3↗