Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Nurul Nadirah Razali ◽  
Ting Tzer Hwu ◽  
Karuppiah Thilakavathy
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Genetic Mutations ◽  
Renal Tubules ◽  
Phosphate Homeostasis ◽  
Tooth Structure ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

AbstractHypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (

Disorders of phosphate metabolism

2019 ◽  
Vol 72 (11) ◽  
pp. 741-747 ◽  
Author(s):  
Jenny Leung ◽  
Martin Crook
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
The Body ◽  
Plasma Phosphate ◽  
Phosphate Homeostasis ◽  
Organic Form ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Renal Tubular Reabsorption ◽  
Renal Tubular ◽  
Storage Pools

Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.

scholarly journals Rare cause of pathological fracture in adults as hypophosphatemic rickets

2019 ◽  
Vol 6 (5) ◽  
pp. 1681
Author(s):  
Jeetendra Kumar J. M. ◽  
Mamatha T. R. ◽  
Divya Sharma K. R. ◽  
Gowtham S. Gowda
Keyword(s):  
Autosomal Recessive ◽  
Pathological Fracture ◽  
Autosomal Dominant ◽  
Fibroblast Growth Factor 23 ◽  
Normal Serum ◽  
Hypophosphatemic Rickets ◽  
Correct Identification ◽  
Recessive Type ◽  
Normal Serum Calcium ◽  
Defective Bone

Hypophosphatemic rickets is a disorder of defective bone minerlization due to defect in renal phosphate handling process. It is characterised by increased phosphate excretion accompanied by increased phosphatonins like fibroblast growth factor 23. It can be hereditary form of X linked, autosomal dominant, autosomal recessive type of hypophosphatemic rickets. It is associated with low serum phosphorus, normal serum calcium, inappropriately low to normal vitamin D level. Correct identification of these disorders is important for determining therapy. Early diagnosis and management prevent subsequent complication of the disease.

scholarly journals Regulation and Function of the FGF23/Klotho Endocrine Pathways

2012 ◽  
Vol 92 (1) ◽  
pp. 131-155 ◽  
Author(s):  
Aline Martin ◽  
Valentin David ◽  
L. Darryl Quarles
Keyword(s):  
Vitamin D ◽  
Intestinal Absorption ◽  
Mineral Metabolism ◽  
Bone Mineralization ◽  
Phosphate Homeostasis ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Tubular Phosphate Reabsorption ◽  
Renal Tubular ◽  
And Function

Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

scholarly journals Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes

2012 ◽  
Vol 28 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Justine Bacchetta ◽  
Jessica L Sea ◽  
Rene F Chun ◽  
Thomas S Lisse ◽  
Katherine Wesseling-Perry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Human Monocytes ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

scholarly journals FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes

2015 ◽  
Vol 226 (3) ◽  
pp. 155-166 ◽  
Author(s):  
Ichiro Kaneko ◽  
Rimpi K Saini ◽  
Kristin P Griffin ◽  
G Kerr Whitfield ◽  
Mark R Haussler ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Fibroblast Growth Factor 23 ◽  
K562 Cells ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Surface Acting ◽  
Reporter Construct ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
High Calcium

In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor 23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression and induces C/EBPβ, but does not affect leptin receptor transcription. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between −400 and −200 bp. A 0.6 kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a fourfold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at −346 bp, or an adjacent candidate vitamin D receptor (VDR)/Nurr1-element, in the 0.6 kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1–VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1 kb mouse FGF23 promoter–reporter construct, transfected into MC3T3-E1 osteoblast-like cells, responds to a high calcium challenge with a statistically significant 1.7- to 2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.

scholarly journals The Receptor-Dependent Actions of 1,25-Dihydroxyvitamin D Are Required for Normal Growth Plate Maturation in NPt2a Knockout Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4607-4612 ◽  
Author(s):  
Susanne U. Miedlich ◽  
Eric D. Zhu ◽  
Yves Sabbagh ◽  
Marie B. Demay
Keyword(s):  
Vitamin D ◽  
Growth Plate ◽  
Fibroblast Growth Factor 23 ◽  
Normal Growth ◽  
Chondrocyte Apoptosis ◽  
Apoptotic Pathway ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Hypertrophic Chondrocyte

Rickets is a growth plate abnormality observed in growing animals and humans. Rachitic expansion of the hypertrophic chondrocyte layer of the growth plate, in the setting of hypophosphatemia, is due to impaired apoptosis of these cells. Rickets is observed in humans and mice with X-linked hypophosphatemia that is associated with renal phosphate wasting secondary to elevated levels of fibroblast growth factor-23. Rickets is also seen in settings of impaired vitamin D action, due to elevated PTH levels that increase renal phosphate excretion. However, mice with hypophosphatemia secondary to ablation of the renal sodium-dependent phosphate transport protein 2a (Npt2a), have not been reported to develop rickets. Because activation of the mitochondrial apoptotic pathway by phosphate is required for hypertrophic chondrocyte apoptosis in vivo, investigations were undertaken to address this paradox. Analyses of the Npt2a null growth plate demonstrate expansion of the hypertrophic chondrocyte layer at 2 wk of age, with resolution of this abnormality by 5 wk of age. This is temporally associated with an increase in circulating levels of 1,25-dihydroxyvitamin D. To address whether the receptor-dependent actions of this steroid hormone are required for normalization of the growth plate phenotype, the Npt2a null mice were mated with mice lacking the vitamin D receptor or were rendered vitamin D deficient. These studies demonstrate that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for maintenance of a normal growth plate phenotype in the Npt2a null mice.

scholarly journals Mineralizing Enthesopathy Is a Common Feature of Renal Phosphate-Wasting Disorders Attributed to FGF23 and Is Exacerbated by Standard Therapy in Hyp Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5906-5917 ◽  
Author(s):  
Andrew C. Karaplis ◽  
Xiuying Bai ◽  
Jean-Pierre Falet ◽  
Carolyn M. Macica
Keyword(s):  
Standard Therapy ◽  
Autosomal Recessive ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Phex Gene ◽  
Dentin Matrix ◽  
Insertion Sites ◽  
Autosomal Recessive Hypophosphatemic Rickets ◽  
The Impact ◽  
Inactivating Mutations

Abstract We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy.

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