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1.
Clin Calcium ; 22(1): 11-7, 2012 Jan.
Artículo en Japonés | MEDLINE | ID: mdl-22201094

RESUMEN

Tight regulation of serum concentrations of calcium and phosphate is indispensable for maintaining normal physiological condition. Imbalance of this regulation leads to pathophysiological disorders including heart disease, chronic kidney disease, and ectopic calcification. Formation and mineralization of bone and tooth are greatly influenced by calcium and phosphate metabolism since both organs are mainly consist of calcium-phosphate. Calcium and phosphate homeostasis is under hormonal control on its target organs such as kidney, bone and intestine. Calcium and phosphate are absorbed in intestine and reabsorbed and excreted in kidney. Bone store and release them in response to changing physiological demand by osteoblastic bone formation and osteoclastic bone resorption. Bone is also important as an endocrine organ that releases FGF23 from osteocytes, a novel hormone that targets the kidney to inhibit phosphate reabsorption and 1α, 25 (OH) (2)D(3) production.


Asunto(s)
Huesos/metabolismo , Calcio/metabolismo , Homeostasis/fisiología , Fosfatos/metabolismo , Diente/metabolismo , Resorción Ósea , Calcitonina/fisiología , Calcitriol/biosíntesis , Calcio/sangre , Proteínas de la Matriz Extracelular/fisiología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/fisiología , Humanos , Riñón/metabolismo , Osteocitos/metabolismo , Osteogénesis , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Hormona Paratiroidea/fisiología , Fosfatos/sangre , Fosfoproteínas/fisiología
2.
Am J Physiol Renal Physiol ; 300(3): F783-91, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21177780

RESUMEN

Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphate-regulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEX-dependent hypophosphatemia in normal mice. Male mice (n = 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D(3) diet (1% P(i) diet) or a reduced phosphorus and vitamin D(3) diet (0.1% P(i) diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg·day(-1)·kg(-1)) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P(i) diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P(i) diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D(3) [1,25 (OH)(2)D(3)] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; +50%) and reduced serum osteocalcin (-30%) and osteopontin (-25%). Circulating ASARM peptides showed a significant inverse correlation with serum P(i) and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEX-independent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation.


Asunto(s)
Ácido Aspártico , Proteínas de la Matriz Extracelular/fisiología , Glicoproteínas/fisiología , Riñón/metabolismo , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Péptidos/fisiología , Fosfatos/sangre , Fosfoproteínas/fisiología , Serina , Secuencia de Aminoácidos , Animales , Proteínas de la Matriz Extracelular/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Hipofosfatemia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Datos de Secuencia Molecular , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo
3.
J Clin Invest ; 118(2): 722-34, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18172553

RESUMEN

Patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a model of XLH characterized by a deletion in the Phex gene, manifest hypophosphatemia, renal phosphate wasting, and rickets/osteomalacia. Cloning of the PHEX/Phex gene and mutations in affected patients and hyp-mice established that alterations in PHEX/Phex expression underlie XLH. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH. To establish whether abnormal Phex in osteoblasts and/or osteocytes alone generates the HYP phenotype, we created mice with a global Phex knockout (Cre-PhexDeltaflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexDeltaflox/y). Serum phosphorus levels in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-PhexDeltaflox/y and OC-Cre-PhexDeltaflox/y mice was associated with increased bone production and serum FGF-23 levels and decreased kidney membrane type IIa sodium phosphate cotransporter protein, as was the case in hyp-mice. In addition, Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice manifested comparable osteomalacia. These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype.


Asunto(s)
Huesos/patología , Raquitismo Hipofosfatémico Familiar/enzimología , Enfermedades Genéticas Ligadas al Cromosoma X , Osteoblastos/enzimología , Osteocitos/enzimología , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Vitamina D/metabolismo , Animales , Transporte Biológico , Huesos/anomalías , Huesos/diagnóstico por imagen , Modelos Animales de Enfermedad , Fémur/anomalías , Fémur/diagnóstico por imagen , Fémur/patología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/metabolismo , Riñón/metabolismo , Ratones , Ratones Noqueados , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Fósforo/sangre , Fósforo/metabolismo , Radiografía
4.
Eur J Clin Invest ; 40(6): 552-60, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20412291

RESUMEN

BACKGROUND: Renal reabsorption of inorganic phosphate is critical for the maintenance of phosphate homeostasis. The sodium dependent phosphate cotransporters NaPi-IIa and NaPi-IIc have been identified to fulfill this task at the brush border membrane of proximal tubule cells. Various factors including dietary phosphate intake, parathyroid hormone, or the so called phosphatonins such as FGF23 have been shown to regulate activity of these transporters. DESIGN: This review seeks to give an update on our current knowledge about regulatory mechanisms involved in human renal phosphate reabsorption. RESULTS: Recently, an increasing number of genes have been identified that are directly associated with inherited phosphate wasting disorders (Klotho, PHEX, DMP1 and NHERF1). Several of these genes are predominantly expressed by osteocytes and osteoclasts in the bone suggesting indispensable signalling pathways between kidneys and the skeleton. CONCLUSION: In this review, the affected gene products in these inherited hypophosphataemias and their contribution to phosphate homeostasis are discussed.


Asunto(s)
Hipofosfatemia/metabolismo , Riñón/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Fosfatos/metabolismo , Raquitismo/metabolismo , Proteínas de la Matriz Extracelular/fisiología , Raquitismo Hipofosfatémico Familiar/fisiopatología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/fisiología , Glucuronidasa/fisiología , Humanos , Hipofosfatemia/genética , Proteínas Klotho , Nefrolitiasis/fisiopatología , Osteoporosis/fisiopatología , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Fosfoproteínas/fisiología , Raquitismo/fisiopatología , Intercambiadores de Sodio-Hidrógeno/fisiología
5.
FASEB J ; 23(11): 3702-11, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19584304

RESUMEN

Hyp mice possess a mutation that inactivates the phosphate-regulating gene, which is homologous to the endopeptidases of the X-chromosome (PHEX). The mutation is associated with severe hypophosphatemia due to excessive urinary phosphate wasting. Such urinary phosphate wasting in Hyp mice is associated with an increased serum accumulation of fibroblast growth factor (FGF) 23. We wanted to determine the biological significance of increased serum FGF23 levels and concomitant hypophosphatemia in Hyp mice and to evaluate whether FGF23 activity could be modified by manipulating klotho (a cofactor of FGF23 signaling). We generated Hyp and klotho double-mutant mice (Hyp/klotho(-/-)). Severe hypophosphatemia of Hyp mice was reversed to hyperphosphatemia in Hyp/klotho(-/-) double mutants, despite the fact that the double mutants showed significantly increased serum levels of FGF23. Hyperphosphatemia in Hyp/klotho(-/-) mice was associated with increased renal expression of sodium/phosphate cotransporter 2a (NaPi2a) protein. Exogenous injection of bioactive parathyroid hormone 1-34 down-regulated renal expression of NaPi2a and consequently reduced serum levels of phosphate in Hyp/klotho(-/-) mice. Moreover, in contrast to the Hyp mice, the Hyp/klotho(-/-) mice showed significantly higher serum levels of 1,25-dihydroxyvitamin D and developed extensive calcification in soft tissues and vascular walls. Furthermore, compared with the Hyp mice, Hyp/klotho(-/-) mice were smaller in size, showed features of generalized tissue atrophy, and generally died by 15-20 wk of age. Our in vivo studies provide genetic evidence for a pathological role of increased FGF23 activities in regulating abnormal phosphate homeostasis in Hyp mice. Moreover, these results suggest that even when serum levels of FGF23 are significantly high, in the absence of klotho, FGF23 is unable to regulate systemic phosphate homeostasis. Our in vivo observations have significant clinical implications in diseases associated with increased FGF23 activity and suggest that the functions of FGF23 can be therapeutically modulated by manipulating the effects of klotho.


Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Glucuronidasa/fisiología , Hipofosfatemia/metabolismo , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Animales , Calcio/sangre , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/fisiología , Hipofosfatemia/genética , Proteínas Klotho , Ratones , Ratones Noqueados , Fosfatos/sangre , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Vitamina D/análogos & derivados , Vitamina D/sangre
6.
Curr Opin Nephrol Hypertens ; 18(4): 285-91, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19448536

RESUMEN

Osteocytes, the terminally differentiated cell of the osteoblast lineage, account for over 90% of all bone cells. Due to their relative inaccessibility within mineralized matrix, little is known regarding their specific functions in comparison to the well studied surface bone cells, osteoblasts and osteoclasts. Furthermore, bone is often viewed as a mineral reservoir that passively releases calcium and phosphate in response to hormones secreted from remote organs. Noncollagenous matrix proteins produced in osteocytes, such as dentin matrix protein 1 (DMP1), have also been viewed as inert scaffolds for calcium-phosphate deposition. Recent discoveries of new genetic mutations in human diseases and development of genetically engineered animal models challenge these classic paradigms, suggesting that the osteocyte plays an active role in both mineralization and total systemic phosphate regulation. In this review, we will focus on roles of osteocytes in mineralization and particularly in phosphate regulation via the DMP1- FGF23 pathway.


Asunto(s)
Homeostasis , Osteocitos/metabolismo , Fosfatos/metabolismo , Animales , Calcificación Fisiológica , Linaje de la Célula , Enfermedad Crónica , Proteínas de la Matriz Extracelular/fisiología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/fisiología , Glicoproteínas/fisiología , Humanos , Enfermedades Renales/etiología , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Fosfoproteínas/fisiología
7.
Contrib Nephrol ; 180: 124-37, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23652555

RESUMEN

Deregulated phosphate homeostasis can lead to a wide range of disorders, including myopathy, cardiac dysfunction, and skeletal abnormalities. Therefore, characterization of the molecular regulation of phosphate metabolism is of pathophysiological and clinical significance. Hyp mouse is the model for human X-linked hypophosphatemia which is due to mutations that inactivate the endopeptidases of the X chromosome (PHEX). PHEX inactivation leads to increased serum levels of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. The expression of WNT signaling components is increased in Hyp mice. To determine the potential role of WNT signaling in FGF23-mediated hypophosphatemia, we cross-bred Hyp mice with mice deficient in the WNT coreceptor low-density lipoprotein receptor-related protein 6 (Lrp6) to generate Hyp and Lrp6 double mutant mice (Hyp/Lrp6). Like Hyp mice, Hyp/Lrp6 double mutants maintained high serum levels of FGF23, and accordingly exhibited hypophosphatemia to the same degree as the Hyp mice did, indicating that genetically reducing WNT signaling does not impact FGF23-induced phosphaturia. Moreover, similar to Hyp mice, the Hyp/Lrp6 double mutants also exhibited reduced mineralization of the bone, further supporting that reduced WNT signaling does not affect the chronic phosphate wasting caused by excess FGF23 in these mice. In further support of our finding, injection of bioactive FGF23 protein into Lrp6 mutant mice reduced serum phosphate levels to a similar degree as FGF23 injection into wild-type mice. Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis.


Asunto(s)
Modelos Animales de Enfermedad , Raquitismo Hipofosfatémico Familiar/fisiopatología , Factores de Crecimiento de Fibroblastos/fisiología , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/deficiencia , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Vía de Señalización Wnt , Animales , Raquitismo Hipofosfatémico Familiar/diagnóstico por imagen , Raquitismo Hipofosfatémico Familiar/etiología , Raquitismo Hipofosfatémico Familiar/genética , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/toxicidad , Homeostasis , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Riñón/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/fisiología , Masculino , Ratones , Ratones Noqueados , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/metabolismo , Radiografía , Proteínas Recombinantes/toxicidad , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo II/biosíntesis , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo II/genética
10.
Endocrinology ; 150(9): 4012-23, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19520780

RESUMEN

Increased matrix extracellular phosphoglycoprotein (MEPE) expression occurs in several phosphate and bone-mineral metabolic disorders. To resolve whether MEPE plays a role, we created a murine model overexpressing MEPE protein (MEPE tgn) in bone. MEPE tgn mice displayed a growth and mineralization defect with altered bone-renal vascularization that persisted to adulthood. The growth mineralization defect was due to a decrease in bone remodeling, and MEPE tgn mice were resistant to diet-induced renal calcification. MEPE protein-derived urinary ASARM peptides and reduced urinary Ca X PO4 product mediated the suppressed renal calcification. Osteoblastic cells displayed reduced activity but normal differentiation. Osteoclastic precursors were unable to differentiate in the presence of osteoblasts. In the kidney, NPT2a up-regulation induced an increase in phosphate renal reabsorption, leading to hyperphosphatemia. We conclude MEPE and MEPE-phosphate-regulating gene with homologies to endopeptidases on the X chromosome (MEPE-PHEX) interactions are components to an age-diet-dependent pathway that regulates bone turnover and mineralization and suppresses renal calcification. This novel pathway also modulates bone-renal vascularization and bone turnover.


Asunto(s)
Proteínas de la Matriz Extracelular/fisiología , Glicoproteínas/fisiología , Fosfoproteínas/fisiología , Envejecimiento , Aldosterona/orina , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Desarrollo Óseo/efectos de los fármacos , Huesos/irrigación sanguínea , Calcitriol/sangre , Hiperfosfatemia/fisiopatología , Hipocalcemia/fisiopatología , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Patológica/genética , Osteopontina/metabolismo , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Hormona Paratiroidea/sangre , Factor A de Crecimiento Endotelial Vascular/sangre
11.
Curr Opin Nephrol Hypertens ; 17(4): 357-62, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18660670

RESUMEN

PURPOSE OF REVIEW: We aim to review the biological properties of novel molecules that are members of a kidney-bone axis involved in the regulation of phosphate homeostasis. In addition, we describe how an improved knowledge of the mechanisms leading to changes in renal phosphate handling may lead to the development of novel therapeutic approaches. RECENT FINDINGS: As yet, eight genes involved in the regulation of phosphate homeostasis have been identified through genetic studies. A key protein in this regulatory pathway is FGF23, which is made by osteocytes and activates renal KLOTHO/FGFR1 receptor heterodimers to inhibit renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Gain-of-function mutations in FGF23, which render the hormone resistant to proteolytic cleavage, lead to increased phosphaturic activity. Furthermore, inactivating mutations in DMP1 and PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion. In contrast, loss-of-function mutations in FGF23 and KLOTHO, and abnormal O-glycosylation of FGF23 because of GALNT3 mutations, lead to diminished phosphate excretion. Extremely high levels of FGF23 are observed in chronic renal failure, which may contribute to the development of renal osteodystrophy. SUMMARY: The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis, although it is not yet completely understood how these proteins interact, and additional proteins are likely to contribute to these regulatory events.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/fisiología , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/fisiología , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Glándulas Paratiroides/fisiología , Hormona Paratiroidea/fisiología , Fosfoproteínas/genética , Fosfoproteínas/fisiología , Animales , Calcitriol/biosíntesis , Proteínas de la Matriz Extracelular/sangre , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Glicoproteínas/genética , Glicoproteínas/fisiología , Humanos , Fallo Renal Crónico/genética , Fallo Renal Crónico/metabolismo , Endopeptidasa Neutra Reguladora de Fosfato PHEX/sangre , Hormona Paratiroidea/sangre , Fosfoproteínas/sangre
12.
Curr Opin Pediatr ; 19(4): 488-91, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17630616

RESUMEN

PURPOSE OF REVIEW: Unlike calcium metabolism, the control of phosphate homeostasis has long been poorly understood. The identification of 'phosphatonins' in the serum of hypophosphatemic patients, the unveiling of the genetic causes of hypo and hyperphosphatemic diseases in patients, and the creation of finely adapted animal models have revolutionized our understanding of phosphate homeostasis. RECENT FINDINGS: Original reports published in 2006/2007 bring valuable pieces of information that enable better understanding of the physiological regulation of phosphate homeostasis by more precisely defining the interplay between PHEX, vitamin D, and phosphatonins; identification of new genes causing hypophosphatemic rickets, aside from PHEX and fgf23, namely the genes encoding for a renal sodium-phosphate cotransporter, NaPiIIc, and for a bone matrix protein, DmpI; and improved diagnosis of tumor-induced osteomalacia with more precise imaging techniques for tumor localization and more precise fibroblast growth factor 23 assays. SUMMARY: From a clinical point of view, these findings offer new tools for the diagnosis of hypophosphatemic rickets (biologic, genetic, imaging techniques) and open the way to new treatment strategies.


Asunto(s)
Hipofosfatemia/fisiopatología , Fosfatos/fisiología , Adolescente , Niño , Raquitismo Hipofosfatémico Familiar/genética , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Homeostasis , Humanos , Hipofosfatemia/diagnóstico , Hipofosfatemia/etiología , Hipofosfatemia/genética , Lactante , Osteomalacia/etiología , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología
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