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Calciotropic and phosphotropic hormones in fetal and neonatal bone development.
Ryan, BA, Kovacs, CS
Seminars in fetal & neonatal medicine. 2020;(1):101062
Abstract
There are remarkable differences in bone and mineral metabolism between the fetus and adult. The fetal mineral supply is from active transport across the placenta. Calcium, phosphorus, and magnesium circulate at higher levels in the fetus compared to the mother. These high concentrations enable the skeleton to accrete required minerals before birth. Known key regulators in the adult include parathyroid hormone (PTH), calcitriol, fibroblast growth factor-23, calcitonin, and the sex steroids. But during fetal life, PTH plays a lesser role while the others appear to be unimportant. Instead, PTH-related protein (PTHrP) plays a critical role. After birth, serum calcium falls and phosphorus rises, which trigger an increase in PTH and a subsequent rise in calcitriol. The intestines become the main source of mineral supply while the kidneys reabsorb filtered minerals. This striking developmental switch is triggered by loss of the placenta, onset of breathing, and the drop in serum calcium.
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2.
X-Linked Hypophosphataemic Rickets and Growth.
Santos Rodríguez, F
Advances in therapy. 2020;(Suppl 2):55-61
Abstract
X-linked hypophosphataemia (XLH) is the most prevalent form of hereditary rickets characterized by an alteration of phosphate metabolism which frequently leads to the appearance of fractures, bone deformities and growth delay. Although the mechanism of growth impairment in patients with XLH still needs to be clarified, it is known that this alteration is not due to genetic or endocrine factors. A potential explanation for the impairment of growth in this disease is the alteration of the growth plate, a structure responsible for longitudinal growth of bones. Some of the findings in the growth plate of patients with XLH include atypical organization of chondrocytes due to low rates of proliferation and apoptosis and disturbance of chondrocyte hypertrophy, overactivation of the mitogen-activated protein kinase (MAPK) signalling pathway and upregulation of phosphorylated extracellular signal-regulated kinase (pERK). Conventional treatment of XLH (consisting of oral phosphate supplements and active vitamin D analogues) is often insufficient for the longitudinal growth of bone, but other strategies based on recombinant growth hormone or therapies targeting fibroblast growth factor 23 (FGF23) or its receptor, such as burosumab, have shown promising results. This article briefly describes the relationship between XLH and growth retardation, and how to address this alteration in patients with XLH.
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Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease.
Courbon, G, Martinez-Calle, M, David, V
Current opinion in nephrology and hypertension. 2020;(4):359-366
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Abstract
PURPOSE OF REVIEW Hyperphosphatemia, iron deficiency, and anemia are powerful stimuli of fibroblast growth factor 23 (FGF23) production and are highly prevalent complications of chronic kidney disease (CKD). In this manuscript, we put in perspective the newest insights on FGF23 regulation by iron and phosphate and their effects on CKD progression and associated outcomes. We especially focus on new studies aiming to reduce FGF23 levels, and we present new data that suggest major benefits of combined corrections of iron, phosphate, and FGF23 in CKD. RECENT FINDINGS New studies show that simultaneously correcting iron deficiency and hyperphosphatemia in CKD reduces the magnitude of FGF23 increase. Promising therapies using iron-based phosphate binders in CKD might mitigate cardiac and renal injury and improve survival. SUMMARY New strategies to lower FGF23 have emerged, and we discuss their benefits and risks in the context of CKD. Novel clinical and preclinical studies highlight the effects of phosphate restriction and iron repletion on FGF23 regulation.
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4.
Calcium and Phosphate Hormones: Vitamin D, Parathyroid Hormone, and Fibroblast Growth Factor 23.
Underland, L, Markowitz, M, Gensure, R
Pediatrics in review. 2020;(1):3-11
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Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease.
Babitt, JL, Sitara, D
Current opinion in nephrology and hypertension. 2019;(4):304-310
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Abstract
PURPOSE OF REVIEW Recent research has revealed that regulation of the bone-secreted hormone fibroblast growth factor 23 (FGF23) is not limited to classical mineral factors. Specifically, bidirectional relationships have been described between FGF23 production and anemia, iron status, and inflammation. Here, we will review the latest published articles on the crosstalk between FGF23 and the aforementioned nonclassical factors. RECENT FINDINGS It has been recently reported that erythropoietin, iron deficiency, and inflammation increase FGF23 production and metabolism. Moreover, FGF23 promotes anemia and regulates inflammatory responses. These findings are particularly important in the setting of chronic kidney disease which is characterized by elevated FGF23 levels and several associated comorbidities. SUMMARY Regulation of FGF23 is complex and involves many bone and renal factors. More recently, erythropoietin, iron deficiency, and inflammation have been also shown to affect FGF23 transcription and cleavage. Importantly, FGF23 has emerged as a regulator of erythropoiesis, iron metabolism, and inflammation. These findings provide novel and important insights into the pathophysiologic mechanisms of chronic kidney disease and may present new opportunities for therapeutic clinical interventions.
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6.
FGF23 and Phosphate-Cardiovascular Toxins in CKD.
Vogt, I, Haffner, D, Leifheit-Nestler, M
Toxins. 2019;(11)
Abstract
Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages of CKD, FGF23 prevents the increase of serum phosphate levels and thereby attenuates phosphate-induced vascular calcification, whereas in end-stage kidney disease, FGF23 fails to maintain phosphate homeostasis. Both hyperphosphatemia and elevated FGF23 levels promote the development of hypertension, vascular calcification, and left ventricular hypertrophy by distinct mechanisms. Therefore, FGF23 and phosphate are considered promising therapeutic targets to improve the cardiovascular outcome in CKD patients. Previous therapeutic strategies are based on dietary and pharmacological reduction of serum phosphate, and consequently FGF23 levels. However, clinical trials proving the effects on the cardiovascular outcome are lacking. Recent publications provide evidence for new promising therapeutic interventions, such as magnesium supplementation and direct targeting of phosphate and FGF receptors to prevent toxicity of FGF23 and hyperphosphatemia in CKD patients.
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Earlier Onset in Autosomal Dominant Hypophosphatemic Rickets of R179 than R176 Mutations in Fibroblast Growth Factor 23: Report of 20 Chinese Cases and Review of the Literature.
Liu, C, Zhao, Z, Wang, O, Li, M, Xing, X, Hsieh, E, Fukumoto, S, Jiang, Y, Xia, W
Calcified tissue international. 2019;(5):476-486
Abstract
Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disorder characterized by variant onset ages and diverse phenotypes. Our aim is to explore the genotype-phenotype correlations between ADHR patients with R176 and R179 mutations in FGF23 gene. Clinical manifestations, laboratory examinations, and genetic analyses were collected from 20 patients in six Chinese ADHR kindreds in our hospital. Previously published ADHR literatures were reviewed. Among 20 Chinese ADHR mutation carriers, 11 patients revealed overt symptoms. 10/11 (90.9%) of which were females. Patients with R179 mutations presented with earlier onset than those with R176 mutation [1.3 (1.0, 37.0) years vs. 28.5 (19.0, 44.0) years]. More patients with R179 mutations had a history of rickets with lower extremity deformity [3/4 (75%) vs. 1/7 (14.3%), p < 0.05]. The serum phosphate, i-FGF23 and c-FGF23 levels of patients with R179 and R176 mutations were 0.47 ± 0.14 mmol/L versus 0.57 ± 0.17 mmol/L, 79.6 ± 87.0 pg/mL versus 79.9 ± 107.4 pg/mL, and 33.4 ± 3.0 RU/mL versus 121.3 ± 177.6 RU/mL, respectively. 7/11 of patients had iron deficiency at onset of disease. When combined with previously reported seven ADHR families, difference was observed in the age of onset among symptomatic patients with R179 and R176 mutations [1.0 (0.9, 37.0) years vs. 24.5 (1.2, 57.0) years, p < 0.05]. Patients with R179 mutation were more likely to have rickets than R176 mutation (11/13, 84.6% vs. 5/20, 25.0%, p < 0.01) and lower extremity deformity (10/13, 76.9% vs. 6/19, 31.6%, p < 0.01). ADHR patients with R179 mutations had earlier onset age and more rickets compared to those with mutations in R176, which partially explained the clinical heterogeneity of ADHR.
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Renal and extrarenal effects of fibroblast growth factor 23.
Vervloet, M
Nature reviews. Nephrology. 2019;(2):109-120
Abstract
Fibroblast growth factor 23 (FGF23) is a hormone with a central role in the regulation of phosphate homeostasis. This regulation is accomplished by the coordinated modulation of renal phosphate handling, vitamin D metabolism and parathyroid hormone secretion. Patients with kidney disease have increased circulating levels of FGF23 and in other patient populations and in healthy individuals, FGF23 levels also rise following an increase in dietary phosphate intake. Maladaptive increases in FGF23 have a detrimental effect on several organs and tissues and, importantly, these pathological changes most likely contribute to increased morbidity and mortality. For example, in the context of heart disease, FGF23 is involved in the development of pathological hypertrophy that can lead to congestive heart failure. Increased FGF23 concentrations can also lead to microcirculatory changes, in particular reduced vasodilatory capacity, and collectively these cardiovascular changes can compromise tissue perfusion. In addition, FGF23 is associated with inflammation and an increased risk of infection; other potentially detrimental effects of FGF23 are likely to emerge in the future. Most importantly, recent insights demonstrate that FGF23 can be therapeutically targeted, which holds promise for the treatment of many patients in a variety of clinical settings.
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Phosphaturic Mesenchymal Tumor of Soft Tissue of the Foot: Report of a Case With Review of the Literature.
Bisceglia, M, Galliani, CA, Fraternali Orcioni, G, Perrone, E, Del Giudice, A, Scillitani, A
Advances in anatomic pathology. 2019;(5):320-328
Abstract
Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that ectopically secretes fibroblast growth factor 23, a bone cell-derived protein that regulates phosphate homeostasis. The overproduction of fibroblast growth factor 23 causes a paraneoplastic syndrome characterized by hyperphosphaturia, hypophosphatemia, hypovitaminosis D, and vitamin D refractory rickets/osteomalacia, effects that disappear with tumor removal. The PMT may occur in several anatomic regions, mainly in the limbs, usually involving both soft tissue and bone. Acral locations occur in 10% to 15% of the cases, mostly in the feet, with 95 cases reported in this anatomic region to date. We report a case of a PMT in a young adult male who presented in 2007 with the classic constellation of signs and symptoms. A small soft-tissue tumor was detected in his right heel, 3 years after exhaustively seeking for it by various imaging techniques performed at different institutions. Before the tumor was detected, attempts to manage this patient's osteomalacia with phosphate and vitamin D (both calcitriol and ergocalciferol) supplementation were unsuccessful. Following surgical resection, the patient experienced prompt correction of the phosphaturia and gradual reconstitution of his bone mineralization. The pathologic diagnosis was (benign) PMT, mixed connective tissue type. In 2019, 12 years after resection, the patient is asymptomatic, and his bone mineral homeostasis has been restored.
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10.
[Novel hormones related to the calcium and phosphate homeostasis in kidney disease].
Mace, ML, Ølgaard, K, Lewin, E
Ugeskrift for laeger. 2018;(21)
Abstract
Calcium and phosphate levels are regulated by a complex interplay between parathyroid hormone (PTH), calcitriol, fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho. Kidney failure causes severe disturbances in the mineral and bone homeostasis resulting in phosphate retention, hypocalcaemia and high plasma levels of FGF23 and PTH, and the patients develop fragile bones and vascular calcifications. Today's treatments aim to lower the levels of phosphate and PTH. Future studies need to clarify, if lowering the FGF23 level or supplementation with αKlotho will improve survival for patients with chronic kidney disease.