RESUMO
Congenital hypophosphataemia (CH) is a collection of disorders that cause defective bone mineralisation manifesting with rickets in childhood and osteomalacia in adulthood. Bone turnover markers (BTMs) are surrogate measures of metabolic bone disease severity. We explored the utility of BTMs in 27 adults with CH: 23 had X-linked hypophosphataemia (XLH), of whom 2 were hypoparathyroid post-total parathyroidectomy (PTx); 2 had autosomal dominant hypophosphataemic rickets (ADHR), and 2 had none of the known mutations. We measured the renal tubular maximum reabsorption rate of phosphate (TmP/GFR), C-terminal fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), ionised calcium, 1,25-dihydroxyvitamin D [1,25(OH)2D], and a panel of BTMs: serum bone-specific alkaline phosphatase (bone ALP), osteocalcin (Oc), total procollagen type I amino-terminal propeptide (PINP), and carboxy-terminal telopeptide of type I collagen (CTX); and urine amino-terminal telopeptides of type I collagen (uNTX). After excluding 2 patients with XLH and PTx, the frequency of abnormal elevation in BTMs was: bone ALP (96%); CTX (72%); PINP (52%); uNTX (48%); Oc (28%). The strongest association with bone ALP was TmP/GFR. Those patients receiving phosphate supplements and alfacalcidol had significant elevation in CTX. The 2 patients with XLH and PTx had normalisation of TmP/GFR and near normalisation of BTMs post-operatively, despite marked elevation in both C-terminal and intact FGF23. In conclusion, BTMs in our CH patients indicated that most have abnormalities consistent with osteomalacia and many have mild secondary hyperparathyroidism; and the normalisation of TmP/GFR after total PTx in 2 cases of XLH remains unexplained, but possible causes are speculated.
Assuntos
Biomarcadores/metabolismo , Remodelação Óssea , Hipofosfatemia Familiar/metabolismo , Rim/patologia , Paratireoidectomia/efeitos adversos , Fosfatos/metabolismo , Adolescente , Adulto , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia Familiar/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The addition of phosphate groups is an essential requirement for the proper functioning of cyclin and cyclin dependent kinase which control various stages in the mitotic division of cancer cells. Thus limiting the availability of phosphate is likely to interfere with the metabolism of rapidly growing malignant cells. The human hormone glucagon and the anti metabolite mithramycin reduce serum phosphate by increasing phosphaturia and are both very effective in treating Paget's disease of bone, a precancerous condition. In this disorder large doses of glucagon given intravenously relieve bone pain and cause serum phosphate and alkaline phosphatase as well as urine hydroxyproline to fall, indicating a marked reduction in bone turnover. A constant iv infusion of glucagon was given to each of three patients all of whom had secondary malignant bone deposits. Two of the patients had primary prostate cancer and one had a squamous cell lung tumour. All three patients had relief of bone pain and a fall in serum alkaline phosphatase. Serum acid phosphatase also fell in the two patients with prostate cancer. It is proposed that the marked drop in serum phosphate due to glucagon causes intracellular phosphate to fall. This in turn disrupts the addition and removal of phosphate groups essential for the proper functioning of cyclin and cyclin dependent kinase. These two proteins control the transition from G1 to S (DNA synthesis phase) and G2 to M (mitotic phase) in the dividing cycle of malignant cells. Depriving a tumour of an essential ingredient used in phosphorylation reactions will disrupt its growth. It is also proposed that, by the same mechanism, glucagon induced hypophosphataemia renders malignant cells more sensitive to established chemotherapeutic agents and radiation waves. If this hypothesis proves to be correct, lowering intracellular phosphate may become an useful tool in cancer therapy. However extensive studies are necessary to determine whether mitosis in cancer cells can be advantageously disrupted by glucagon induced hypophosphataemia.
Assuntos
Mitose , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosfatos/química , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Osso e Ossos/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Glucagon/química , Glucagon/metabolismo , Humanos , Hidroxiprolina/urina , Hipofosfatemia Familiar/metabolismo , Insulina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Modelos Teóricos , Neoplasias/metabolismo , Osteíte Deformante/tratamento farmacológico , Fosforilação , Neoplasias da Próstata/tratamento farmacológicoRESUMO
The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; α-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads.
Assuntos
Fosfatos/sangue , Fosfatos/metabolismo , Administração Intravenosa , Adulto , Duodeno/efeitos dos fármacos , Eletrólitos/química , Sistema Endócrino/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Taxa de Filtração Glomerular , Glucuronidase/metabolismo , Humanos , Hipocalcemia/metabolismo , Hipofosfatemia/metabolismo , Hipofosfatemia Familiar/metabolismo , Infusões Intravenosas , Proteínas Klotho , Masculino , Hormônio Paratireóideo/metabolismo , Fosfatos/urina , Fatores de Tempo , Adulto JovemRESUMO
Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome associated with tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23). The majority of tumors associated with this syndrome show stereotypical histological features and are now known as phosphaturic mesenchymal tumors (PMTs). We postulated that immunohistochemistry for somatostatin receptor 2A (SSTR2A) could be used to definitively identify PMTs or other tumors that cause TIO. Immunohistochemistry for FGF23 and SSTR2A was performed on 15 tumors from 14 patients with a definite diagnosis of TIO. All showed positive staining for both markers. While FGF23 staining was quite focal in some tumors, SSTR2A showed diffuse strong expression. In 40 control tumors not known to be associated with the clinical or biochemical features of TIO, FGF23 expression was found in 2 cases (one aneurysmal bone cyst and one osteosarcoma). SSTR2A expression was found in 9 control tumors (4 synovial sarcomas, 2 hemangiomas, 2 aneurysmal bone cysts and one osteosarcoma). Only one tumor (an aneurysmal bone cyst) showed positive staining for both FGF23 and SSTR2A. SSTR2A also commonly stained neoplastic and non-neoplastic endothelial cells. We conclude that neither FGF23 nor SSTR2A expression are specific for the diagnosis of PMT. However both stains are highly sensitive. Because of its diffuse strong expression and widespread availability, immunohistochemistry for SSTR2A is useful to confirm the diagnosis of PMT in an appropriate setting particularly if material is limited. Negative staining can serve as an excellent rule out test for this diagnosis.
Assuntos
Hipofosfatemia Familiar/diagnóstico , Mesenquimoma/diagnóstico , Neoplasias de Tecido Conjuntivo/diagnóstico , Osteomalacia/diagnóstico , Síndromes Paraneoplásicas/diagnóstico , Receptores de Somatostatina/metabolismo , Adulto , Medicamentos de Ervas Chinesas , Eleutherococcus , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patologia , Masculino , Mesenquimoma/metabolismo , Mesenquimoma/patologia , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/metabolismo , Neoplasias de Tecido Conjuntivo/patologia , Osteomalacia/metabolismo , Osteomalacia/patologia , Síndromes Paraneoplásicas/metabolismo , Síndromes Paraneoplásicas/patologiaRESUMO
In the present study, we evaluated the roles of type II and type III sodium-dependent P(i) cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a(-/-)Npt2c(-/-) mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent P(i) transporter (PiT2) protein, and renal Na/P(i) transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)(2)D(3) levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein; 2) in DKO mice, renal P(i) reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed; and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)(2)D(3). These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic P(i) homeostasis.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia Familiar/etiologia , Hipofosfatemia/etiologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/deficiência , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/deficiência , Animais , Calcitriol/sangue , Cálcio/sangue , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Técnicas de Transferência de Genes , Humanos , Hipofosfatemia/genética , Hipofosfatemia/metabolismo , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fosfatos/sangue , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genéticaRESUMO
Phosphaturic mesenchymal tumor is an extremely rare disease and is frequently associated with oncogenic osteomalacia showing paraneoplastic syndrome, which is characterized by phosphaturia, hypophosphatemia, normocalcemia, and decreased levels of 1,25-dihydroxyvitamin D3 associated with a tumor. A 2-year-old boy, who had a soft tissue tumor on his right thigh and previously diagnosed as myositis ossificans at 9-months-old, was presented with rachitic rosary and mildly enlarged tumor. Biochemical investigations showed hypophosphatemia, hyperphosphaturia, and an increased alkaline phosphatase level of 440 U/l (25-100 U/l), suggesting rickets, which was resistant to vitamin D dietary supplementation. We were certain of intractable rickets because of oncogenic hypophosphatemia and thus decided to excise the soft tissue mass. We observed laboratory improvement of rickets after 2 weeks. On the basis of surgical and histopathological examinations, the tumor was finally diagnosed as the phosphaturic mesenchymal tumor.
Assuntos
Raquitismo Hipofosfatêmico Familiar/diagnóstico , Hipofosfatemia Familiar/diagnóstico , Mesenquimoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Fosfatase Alcalina/sangue , Pré-Escolar , Diagnóstico Diferencial , Humanos , Hipofosfatemia Familiar/metabolismo , Lactente , Masculino , Mesenquimoma/metabolismo , Mesenquimoma/cirurgia , Miosite Ossificante/diagnóstico , Radiografia Torácica , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/cirurgia , Coxa da Perna/diagnóstico por imagem , Resultado do TratamentoRESUMO
Inactivating mutations of the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) endopeptidase, the disease-causing gene in X-linked hypophosphatemia (XLH), results in increased circulating levels of fibroblastic growth factor-23 (FGF23), a bone-derived phosphaturic factor. To determine the causal role of FGF23 in XLH, we generated a combined Fgf23-deficient enhanced green fluorescent protein (eGFP) reporter and Phex-deficient Hyp mouse model (Fgf23(+/-)/Hyp). eGFP expression was expressed in osteocytes embedded in bone that exhibited marked upregulation of eGFP in response to Phex deficiency and in CD31-positive cells in bone marrow venules that expressed low eGFP levels independently of Phex. In bone marrow stromal cells (BMSCs) derived from Fgf23(-/-)/Hyp mice, eGFP expression was also selectively increased in osteocyte-like cells within mineralization nodules and detected in low levels in CD31-positive cells. Surprisingly, eGFP expression was not increased in cell surface osteoblasts, indicating that Phex deficiency is necessary but not sufficient for increased Fgf23 expression in the osteoblast lineage. Additional factors, associated with either osteocyte differentiation and/or extracellular matrix, are necessary for Phex deficiency to stimulate Fgf23 gene transcription in bone. Regardless, the deletion of Fgf23 from Hyp mice reversed the hypophosphatemia, abnormal 1,25(OH)(2)D(3) levels, rickets, and osteomalacia associated with Phex deficiency. These results suggest that Fgf23 acts downstream of Phex to cause both the renal and bone phenotypes in Hyp mice.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia Familiar/metabolismo , Glicoproteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Osteócitos/fisiologia , Animais , Peso Corporal/fisiologia , Densidade Óssea/fisiologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/fisiologia , Cálcio/sangue , Colecalciferol/sangue , Modelos Animais de Doenças , Feminino , Fêmur/metabolismo , Fêmur/fisiologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Hipofosfatemia Familiar/sangue , Hipofosfatemia Familiar/genética , Masculino , Glicoproteínas de Membrana/genética , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Osteócitos/metabolismo , Endopeptidase Neutra Reguladora de Fosfato PHEX , Hormônio Paratireóideo/sangue , Fósforo/sangue , Regiões Promotoras GenéticasRESUMO
OBJECTIVE: X-linked hypophosphatemic rickets is characterized by renal phosphate wasting, hypophosphatemia and defective bone mineralization. Treatment with oral phosphate (Pi) and calcitriol improves skeletal changes but associates with secondary hyperparathyroidism and nephrocalcinosis. Tertiary hyperparathyroidism is a rare complication of the treatment. The aim of the present study was to identify treatment-related factors that might be associated with the transition of secondary hyperparathyroidism to tertiary hyperparathyroidism in patients with X-linked hypophosphatemic rickets. DESIGN: Thirteen patients with X-linked hypophosphatemic rickets and secondary or tertiary hyperparathyroidism were included in the study. Their hospital records were reviewed and compared for onset, duration and dosage of treatment, and for age of diagnosis and degree of secondary hyperparathyroidism. RESULTS: Two patients developed tertiary hyperparathyroidism and 11 patients secondary hyperparathyroidism during the treatment. Patients with tertiary hyperparathyroidism had, on average, earlier onset and longer duration of treatment, higher dose of Pi and longer duration of treatment with very high Pi doses (> 100 mg/kg/day) compared to the 11 patients with secondary hyperparathyroidism. However, variation of all parameters was great with considerable overlap. Very high S-PTH levels > or = 42 pmol/l were observed in those who later developed tertiary hyperparathyroidism. CONCLUSIONS: Prolonged very high dose oral Pi treatment is a major risk factor for the development of tertiary hyperparathyroidism in X-linked hypophosphatemic rickets.
Assuntos
Hiperparatireoidismo Secundário/induzido quimicamente , Hipofosfatemia Familiar/tratamento farmacológico , Fosfatos/efeitos adversos , Administração Oral , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipofosfatemia Familiar/metabolismo , Lactente , Masculino , Fosfatos/uso terapêuticoRESUMO
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied.
Assuntos
Proteínas de Transporte/genética , Hipofosfatemia Familiar/genética , Simportadores , Sequência de Bases , Cálcio/urina , Análise Mutacional de DNA , Primers do DNA/genética , Feminino , Ligação Genética , Humanos , Hipofosfatemia Familiar/metabolismo , Masculino , Mutação , Linhagem , Fenótipo , Fosfatos/metabolismo , Sódio/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIIRESUMO
Familial hypophosphataemic rickets (XLH) is an X-linked dominant disorder resulting in hypophosphataemia, abnormal regulation of 25-hydroxy vitamin D metabolism, elevated activity of alkaline phosphatase, bone deformities and short stature. In 1995-97 the sequence of PEX gene responsible for the disease was established. The PEX gene spreads 24.3 kb and includes 22 small exons coding a protein belonging to a neutral endopeptidase family. Function of the protein is not known yet. Mutation analysis in patients from North America, Africa and Europe (including Poland) revealed the presence of many different types of the PEX gene mutations. Identified deletions, insertions and substitution are supposed to change the structure of the PEX protein. Active form of vitamin D3, 1-alpha-hydroxylase and phosphate supplementation are now the recommended treatment of XLH patients. Further research is necessary to understand the role of the PEX protein in the pathogenesis of hypophosphatamic rickets.
Assuntos
Hipofosfatemia Familiar/diagnóstico , Hipofosfatemia Familiar/genética , Proteínas/genética , Vitamina D/análogos & derivados , Fosfatase Alcalina/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/terapia , Camundongos , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX , Vitamina D/metabolismoRESUMO
Three patients (a grandmother, her daughter and her grandson) belonging to a 23-number-kindred of five generations suffered from adult-onset, X-linked, familiar hypophosphataemic osteomalacia. According to the familiar anecdotes the great-grandmother also had the same disease. The clinical diagnosis was documented by X-ray pictures, scintigraphic and bone histological results, the laboratory diagnosis was proven by blood and urine analyses examined after phosphate loading. The youngest, 24-year-old patient was treated with daily 3 g phosphate and high doses of calcitriol for 2 years. As a new feature of our therapy, per os treatment with 1.25 micrograms calcitriol was supplemented by daily 2-4 micrograms iv. bolus calcitriol for one week every month. The osteomalacia, causing serious symptoms and complaints, healed. Our treatment seemed to be safe, as renal functions, serum total and ionized calcium and PTH levels (including midnight values) remained in normal range. On the basis of our results this disease can be treated by administration of high doses of phosphate, provided that development of hyperparathyroidism is prevented by the coadministration of high doses of calcitriol.
Assuntos
Calcitriol/administração & dosagem , Hipofosfatemia Familiar/genética , Osteomalacia/genética , Fosfatos/administração & dosagem , Adolescente , Adulto , Cálcio/metabolismo , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/metabolismo , Masculino , Pessoa de Meia-Idade , Osteomalacia/tratamento farmacológico , Osteomalacia/etiologia , Osteomalacia/metabolismo , Linhagem , Fosfatos/metabolismo , Vitamina D/administração & dosagem , Cromossomo XRESUMO
A 41-year-old man presented with back pain, osteoporosis and vertebral crushing. Laboratory studies revealed persistent hypophosphatemia, normocalcemia and elevated levels of 1,25-dihydroxy-vitamin D. Other mineral metabolism tests showed a low tubular maximal phosphate reabsorption per glomerular filtrate, an absorptive hypercalciuria and a normal intestinal absorption of phosphate. Hyperparathyroidism was ruled out by an intravenous calcium loading test. Bone histopathology was consistent with osteomalacia. Treatment with phosphate supplements resulted in resolution of symptoms and normalization of laboratory parameters. To our knowledge, this can be a sporadic form of a disorder recently described: hereditary hypophosphatemic rickets with hypercalciuria.
Assuntos
Distúrbios do Metabolismo do Cálcio/etiologia , Cálcio/urina , Hipofosfatemia Familiar/complicações , Adulto , Calcitriol/sangue , Cálcio/sangue , Creatinina/urina , AMP Cíclico/urina , Taxa de Filtração Glomerular , Humanos , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/metabolismo , Masculino , Fosfatos/uso terapêuticoRESUMO
The effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) administration on duodenal vitamin D receptor (VDR) mRNA levels in hypophosphatemic (Hyp) mice, a murine homologue of human X-linked hypophosphatemic rickets, was examined. Basal levels of VDR mRNA in Hyp mice were similar to those of normal littermates and, in normal mice, VDR mRNA levels were up-regulated 1.8-2.7-fold after injection of 1 microgram/kg 1,25(OH)2D3. In contrast, no significant change in VDR mRNA was observed in Hyp mice treated with 1,25(OH)2D3. To determine the effect of phosphate repletion on VDR mRNA levels, high-phosphate diet was fed to Hyp mice. Although plasma phosphorus concentration was restored to normal, up-regulation of VDR mRNA was not recovered with phosphate supplementation. These results indicate that the vitamin D-resistance in Hyp mice is not caused by hypophosphatemia, per se, and may result from a fundamental molecular defect in vitamin D action at the intestine which could be related to ineffective up-regulation of VDR mRNA by 1,25(OH)2D3.
Assuntos
Calcitriol/farmacologia , Duodeno/metabolismo , Hipofosfatemia Familiar/metabolismo , Fosfatos/sangue , RNA Mensageiro/metabolismo , Receptores de Esteroides/genética , Regulação para Cima/efeitos dos fármacos , Animais , Northern Blotting , Calcitriol/administração & dosagem , Calcitriol/metabolismo , Hipofosfatemia Familiar/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatos/farmacologia , Receptores de Calcitriol , Receptores de Esteroides/biossínteseRESUMO
13 cases of renal tubular osteomalacia, consisting of 5 cases of Vitamin D resistant rickets (VDRR), 6 cases of renal tubular acidosis(RTA) and 2 cases of Fanconis syndrome were reported. The biochemical findings of the serum and urine from the 13 cases were compared with those from normal controls. The clinical findings, diagnosis and treatment of renal tubular osteomalacia were reviewed. The differential diagnosis of osteomalacia with laboratory methods and the mechanism of its pathogenesis were discussed.
Assuntos
Osteomalacia/diagnóstico , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/metabolismo , Adolescente , Adulto , Cálcio/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Hipofosfatemia Familiar/diagnóstico , Hipofosfatemia Familiar/metabolismo , Masculino , Pessoa de Meia-Idade , Osteomalacia/metabolismo , Fósforo/metabolismoRESUMO
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.
Assuntos
Cálcio da Dieta/uso terapêutico , Dentina/anormalidades , Hipofosfatemia Familiar/dietoterapia , Hipofosfatemia Familiar/patologia , Fósforo na Dieta/uso terapêutico , Animais , Densidade Óssea , Cálcio/sangue , Dentina/química , Dentina/ultraestrutura , Feminino , Hipofosfatemia Familiar/sangue , Hipofosfatemia Familiar/metabolismo , Incisivo , Masculino , Mandíbula/química , Mandíbula/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Microscopia Eletrônica de Varredura , Odontoblastos/patologia , Fósforo/sangue , Difração de Raios XRESUMO
Calcium, phosphorus, fluoride, sodium, magnesium and zinc estimations were carried out on teeth from a patient with hypophosphataemic vitamin D-resistant rickets (HVDRR) and from a patient with acquired rickets with the aim of determining differences in the composition of dentine in these two types of rickets. Normal deciduous teeth served as controls. Mineral analyses were carried out using an electron probe micro-analyser after carefully polishing the hemisected specimens. After the analyses the specimens were coated with gold-palladium for more detailed SEM studies. The Ca, P, F and Zn contents of the calcospherites were normal, while there was more Na and less Mg in the dentine of HVDRR teeth than of controls. The significance of this remains unexplained. The mineral content of the interglobular spaces was very limited, but there was more Zn in these than in other parts of the HVDRR teeth, in the acquired rickets teeth or in the control teeth. The excess of Zn in the interglobular spaces is thought to have an effect on the mineralisation process in HVDRR teeth. The globular nature of HVDRR teeth is thought to be genetically controlled and the result of a reduction in the number of calcification nuclei. The globular nature of the HVDRR teeth was not due to lack of Ca and P, as the serum levels of these minerals were maintained within normal limits during tooth development by controlled phosphate supplementation. Because in acquired rickets the globules were seen at the developmental stage that the teeth had reached when the nutritional disturbance occurred, the fault in mineralisation is thought to be different from that in HVDRR teeth.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Dentina/química , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Minerais/análise , Dente Decíduo/química , Cálcio/análise , Criança , Cemento Dentário/química , Cemento Dentário/ultraestrutura , Dentina/ultraestrutura , Dentina Secundária/química , Microanálise por Sonda Eletrônica , Feminino , Flúor/análise , Humanos , Hipofosfatemia Familiar/patologia , Magnésio/análise , Masculino , Microscopia Eletrônica de Varredura , Fósforo/análise , Sódio/análise , Raiz Dentária/química , Raiz Dentária/ultraestrutura , Dente Decíduo/ultraestrutura , Zinco/análiseRESUMO
Over the past decade our understanding of the pathogenesis of altered mineral homeostasis in chronic renal failure (CRF) and X-linked hypophosphatemic vitamin D-resistant rickets (XLH) has increased, and has provided a rational approach for the use of the 1 alpha-hydroxylated analogues of vitamin D in their therapy. Recent evidence suggests that intracellular phosphate (Pi) retention in CRF plays a major role in decreasing serum 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, which are responsible for the progressive rise in serum parathyroid hormone (PTH) concentrations through the direct action of 1,25(OH)2D on the parathyroid gland. 1,25(OH)2D levels affect the number of intracellular 1,25(OH)2D receptors, preproPTH mRNA levels and the set point for calcium suppression of PTH release. Further in experimental CRF, the maintenance of normal 1,25(OH)2D levels prevents parathyroid gland hyperplasia. These studies indicate that depressed renal 1 alpha-hydroxylase activity due to Pi retention is a major factor in directly increasing PTH secretion, which in turn contributes significantly to the severity of renal osteodystrophy. Thus the aim of therapy in early CRF should be to maintain normal levels of 1,25(OH)2D which can be achieved by either dietary Pi restriction and oral Pi binders or by administering small doses of 1 alpha-hydroxylated metabolites. The long term consequences of these two different therapeutic regimens still need to be assessed. In XLH, evidence is rapidly accumulating that alterations in 1 alpha-hydroxylase activity secondary to impaired Pi handling by the proximal renal tubule, results in decreased serum 1,25(OH)2D levels, which might be responsible for a number of the associated abnormalities documented in both treated and untreated XLH patients. These abnormalities include decreased calcium and Pi absorption by the intestine and low normal serum calcium values. In vitamin D- and Pi-treated patients 1,25(OH)2D levels are further depressed, with a resultant increase in PTH values, and the development of tertiary hyperparathyroidism in a small number of patients. The use of 1 alpha-hydroxylated analogues rather than vitamin D together with Pi supplements decreases the severity of hyperparathyroidism, improves Pi absorption from the intestine and markedly ameliorates the degree of osteomalacia. Whether long-term therapy with these analogues will prevent the development of tertiary hyperparathyroidism in patients with XLH is unclear.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Homeostase , Hipofosfatemia Familiar/metabolismo , Rim/metabolismo , Fosfatos/metabolismo , Animais , Calcitriol/sangue , Colestanotriol 26-Mono-Oxigenase , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Humanos , Hiperparatireoidismo/etiologia , Hormônio Paratireóideo/sangue , Esteroide Hidroxilases/metabolismoRESUMO
Hyp mice exhibit increased renal catabolism of vitamin D metabolites by the C-24 oxidation pathway (1988. J. Clin. Invest. 81:461-465). To examine the regulatory influence of dietary phosphate on the renal vitamin D catabolic pathway in Hyp mice, we measured C-24 oxidation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in renal mitochondria isolated from Hyp mice and normal littermates fed diets containing 0.03% (low-Pi), 1% (control-Pi), and 1.6% (high-Pi) phosphate. In normal mice the low-Pi diet led to a rise in serum 1,25(OH)2D (22.2 +/- 1.8 to 48.1 +/- 6.8 pg/ml, P less than 0.05) and no change in C-24 oxidation products (0.053 +/- 0.006 to 0.066 +/- 0.008 pmol/mg protein per min) when compared with the control diet. In Hyp mice the low-Pi diet elicited a fall in serum 1,25(OH)2D (21.9 +/- 1.2 to 8.0 +/- 0.2 pg/ml, P less than 0.05) and a dramatic increase in C-24 oxidation products (0.120 +/- 0.017 to 0.526 +/- 0.053 pmol/mg protein per min, P less than 0.05) when compared with the control diet. The high-Pi diet did not significantly alter serum levels of 1,25(OH)2D or C-24 oxidation products in normal mice. Hyp mice on the high-Pi diet experienced a rise in serum 1,25(OH)2D (21.9 +/- 1.2 to 40.4 +/- 7.3, P less than 0.05) and a fall in C-24 oxidation products (0.120 +/- 0.017 to 0.043 +/- 0.007 pmol/mg protein per min, P less than 0.05). The present results demonstrate that the defect in C-24 oxidation of 1,25(OH)2D3 in Hyp mice is exacerbated by phosphate depletion and corrected by phosphate supplementation. The data suggest that the disorder in vitamin D metabolism in the mutant strain is secondary to the perturbation in phosphate homeostasis.
Assuntos
Hipofosfatemia Familiar/metabolismo , Córtex Renal/metabolismo , Mitocôndrias/metabolismo , Raquitismo/metabolismo , Vitamina D/metabolismo , Cromossomo X , Animais , Calcitriol/sangue , Cálcio/metabolismo , Dieta , Hipofosfatemia Familiar/genética , Masculino , Camundongos , Camundongos Mutantes , Fosfatos/metabolismo , Valores de ReferênciaRESUMO
There have been several reports that document abnormal vitamin D metabolism in X-linked hypophosphatemic rickets (XLH). Those reports indicate a blunted renal 25-hydroxyvitamin D-1 alpha-hydroxylase response to a potent stimulator, phosphorus restriction. We examined here its response to phosphate supplementation. Seven normal volunteers and 12 patients with XLH were submitted to single oral phosphate loading. This treatment produced a marked elevation of the serum phosphorus level, with a mild reduction in the serum calcium level. In normal subjects, although the concentrations of intact parathyroid hormone and mid-region parathyroid hormone were increased, with two peaks at 2 and 8 h after treatment, there were no significant changes in vitamin D metabolites including 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)2D) and 1,25-dihydroxyvitamin D (1,25(OH)2D). On the other hand, in the patients with XLH, the serum 1,25(OH)2D level increased from 23.4 +/- 12.0 (mean +/- SD) pg/ml to 44.3 +/- 33.6 pg/ml 6 h after ingestion without any significant change in 25(OH)D or 24,25(OH)2D.