Tumor-induced osteomalacia

2018 ◽  
Vol 2 (2-3) ◽  
pp. 92-101
Author(s):  
Robert F Reilly
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Parathyroid Hormone ◽  
Growth Factor ◽  
Fusion Protein ◽  
Fibroblast Growth Factor ◽  
Definitive Treatment ◽  
Phosphorus Concentration ◽  
Fibroblast Growth ◽  
Fgf 23

Tumor-induced osteomalacia is a rare paraneoplastic syndrome with approximately 500 cases reported. It presents with a variety of nonspecific symptoms including weakness, muscle and bone pain, and fracture. Characteristic laboratory findings are hypophosphatemia, an elevated alkaline phosphatase, normal parathyroid hormone, normal serum calcium concentration, and an inappropriately low 1,25(OH)2-vitamin D3 concentration. Initially, tumor-induced osteomalacia is misdiagnosed in over 95% of cases. Hypophosphatemia results from renal phosphate wasting occurring as a consequence of FGF-23 production by the tumor. FGF-23 reduces expression and stimulates endocytosis of two sodium-phosphate cotransporters found in the luminal membrane of the proximal tubule resulting in renal phosphate wasting. FGF-23 also inhibits the formation and stimulates the degradation of 1,25(OH)2 vitamin D3. The most common tumor causing tumor-induced osteomalacia is a mixed connective tissue tumor known as a “phosphaturic mesenchymal tumor.” Due to its rarity, it is often misdiagnosed. Molecular studies have shed light on the mechanisms of tumorigenesis with the identification of a fibronectin and fibroblast growth factor receptor 1 fusion protein expressed in about half of cases and a fibronectin and fibroblast growth factor 1 fusion protein in a small subset of tumors. Often small and slow growing, the tumors may be found in unusual locations, such as the extremities and nasal sinuses and are difficult to localize. Definitive treatment involves identification and removal of the tumor. Absent tumor removal, therapeutic goals include improvement of symptoms, raising the serum phosphorus concentration to the lower limit of normal, and maintenance or achievement of normal parathyroid hormone and alkaline phosphatase concentration. Two recent drugs that target pathways involved in the molecular pathogenesis of tumor-induced osteomalacia have recently been developed and are in early-phase clinical trials: the humanized anti-FGF-23 monoclonal antibody burosumab (KRN23) and the FGFR-1,2,3 inhibitor NVP-BGJ398.

scholarly journals Effects of different 1-34 parathyroid hormone dosages on fibroblast growth factor-23 secretion in human bone marrow cells following osteogenic differentiation

2014 ◽  
Vol 6 (2) ◽  
Author(s):  
Frank-Peter Tillmann ◽  
Daniela Hofen ◽  
Monika Herten ◽  
Rüdiger Krauspe ◽  
Marcus Jäger
Keyword(s):  
Bone Marrow ◽  
Vitamin D ◽  
Parathyroid Hormone ◽  
Growth Factor ◽  
Osteogenic Differentiation ◽  
Fibroblast Growth Factor ◽  
Bone Marrow Cells ◽  
Fibroblast Growth ◽  
Trap 5B ◽  
Fgf 23

The importance of fibroblast growth factor (FGF)-23 as part of a hormonal bone-kidney-axis has been well established. Lately, FGF-23 has been suggested as an independent risk factor of death in patients on chronic hemodialysis. Hyperparathyroidism is a common feature of advanced kidney failure or end-stage renal disease. The independent effect of elevated parathyroid hormone (PTH) levels on FGF-23 secretion is still a matter of debate and has not yet been studied in an <em>in</em> <em>vitro</em> model of human bone marrow cells (BMC) during osteogenic differentiation. BMC from three different donors were cultivated for 4 weeks in cell cultures devoid of vitamin D either without 1-34 PTH or with PTH concentrations of 10 or 100 pmol/L, respectively. After 28 days, protein expression of the cells was determined by immunocytochemical staining, whereas real time-polymerase chain reaction served to analyze gene expression of several osteoblastic (osteocalcin, RANKL, Runx-2 and ostase) and osteoclastic markers (RANK, TRAP-5b). The concentrations of FGF-23, ostase and TRAP-5b were determined by ELISA at weeks 2, 3 and 4. We found a basal expression of FGF-23 with no increase in FGF-23 secretion after stimulation with 10 pmol/L 1-34 PTH. Stimulation with 100 pmol/L PTH resulted in an increase in FGF-23 expression (14.1±3.6 pg/mL with no PTH, 13.7±4.0 pg/mL with 10 pmol/L, P=0.84 and 17.6±3.4 pg/mL with 100 pmol/L, P=0.047). These results suggest a vitamin D and PTH-independent FGF-23 expression in human BMC after osteogenic stimulation. As only higher PTH levels stimulated FGF-23 expression, a threshold level might be hypothesized.

scholarly journals 25-vitamin D, 1,25-vitamin D, parathyroid hormone, fibroblast growth factor-23 and cognitive function in men with advanced CKD: a veteran population

2014 ◽  
Vol 82 (2014) (11) ◽  
pp. 296-303 ◽  
Author(s):  
Anna J. Jovanovich ◽  
Michel Chonchol ◽  
Christopher B. Brady ◽  
James D. Kaufman ◽  
Jessica Kendrick ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Cognitive Function ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

2005 ◽  
Vol 288 (6) ◽  
pp. E1101-E1109 ◽  
Author(s):  
Mikiko Ito ◽  
Yuko Sakai ◽  
Mari Furumoto ◽  
Hiroko Segawa ◽  
Sakiko Haito ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Luciferase Reporter ◽  
Fibroblast Growth ◽  
Luciferase Reporter Gene ◽  
Human Carcinoma ◽  
Flanking Region ◽  
Fgf 23

Fibroblast growth factor-23 (FGF-23) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism. To elucidate the precise physiological regulation of FGF-23, we characterized the mouse FGF-23 5′-flanking region and analyzed its promoter activity. The 5′-flanking region of the mouse FGF-23 gene contained a TFIID site (TATA box) and several putative transcription factor binding sites, including MZF1, GATA-1 and c-Ets-1 motifs, but it did not contain the typical sequences of the vitamin D response element. Plasmids encoding 554-bp (pGL/−0.6), 364-bp (pGL/−0.4) and 200-bp (pGL/−0.13) promoter regions containing the TFIID element and +1-bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays. We also found that FGF-23 mRNA was expressed in K-562 erythroleukemia cell lines but not in MC3T3-E1, Raji, or Hep G2 human carcinoma cells. Treatment with 1,25-dihydroxyvitamin D3in the presence of high phosphate markedly stimulated pGL/−0.6 activity, but calcium had no effect. In addition, the plasma FGF-23 levels were affected by the dietary and plasma inorganic phosphate concentrations. Finally, the levels of plasma FGF-23 in vitamin D receptor-null mice were significantly lower than in wild-type mice. The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse FGF-23 gene.

scholarly journals FGF23 as a calciotropic hormone

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1472 ◽  
Author(s):  
María E. Rodríguez-Ortiz ◽  
Mariano Rodríguez
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Calcium Homeostasis ◽  
Bone Cells ◽  
Mineral Metabolism ◽  
Fibroblast Growth Factor 23 ◽  
Calcium Deficiency ◽  
Fibroblast Growth

Maintaining mineral metabolism requires several organs and hormones. Fibroblast growth factor 23 (FGF23) is a phosphatonin produced by bone cells that reduces renal production of calcitriol – 1,25(OH)2D3 – and induces phosphaturia. The consequences of a reduction in 1,25(OH)2D3 involve changes in calcium homeostasis. There are several factors that regulate FGF23: phosphorus, vitamin D, and parathyroid hormone (PTH). More recently, several studies have demonstrated that calcium also modulates FGF23 production. In a situation of calcium deficiency, the presence of 1,25(OH)2D3 is necessary to optimize intestinal absorption of calcium, and FGF23 is decreased to avoid a reduction in 1,25(OH)2D3 levels.

Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption

2018 ◽  
Vol 47 (5) ◽  
pp. 343-351
Author(s):  
Kenneth R. Phelps ◽  
Darius L. Mason
Keyword(s):  
Parathyroid Hormone ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Hyperbolic Equations ◽  
Fibroblast Growth Factor 23 ◽  
Linear Functions ◽  
Hyperbolic Function ◽  
Phosphorus Concentration ◽  
Fibroblast Growth ◽  
Phosphate Reabsorption

Background: The serum phosphorus concentration ([P]s) is the sum of EP/Ccr and TRP/Ccr, where Ccr is creatinine clearance and EP and TRP are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TRP/Ccr, and [PTH] and [FGF23] are linear functions of EP/Ccr. If controls and patients with CKD are considered together, TRP/Ccr is a hyperbolic function of EP/Ccr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23]. Methods: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m2, respectively. All analyses combined both subsets. We measured fasting [PTH] 1–84 and intact [FGF23], and determined contemporaneous EP/Ccr, TRP/Ccr, fractional excretion of phosphorus (FEP), and phosphate tubular maximum per volume of filtrate (TmP/GFR). We examined linear regressions of TRP/Ccr and TmP/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations. Results: TRP/Ccr and TmP/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TRP/Ccr and TmP/GFR fell minimally over the ranges of EP/Ccr, [PTH], and [FGF23] seen in CKD. FEP rose with EP/Ccr despite stable phosphate reabsorption. Conclusions: Hyperbolas describe relationships of TRP/Ccr and TmP/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FEP rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption.

scholarly journals Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism

2006 ◽  
Vol 154 (1) ◽  
pp. 93-99 ◽  
Author(s):  
Keisuke Kobayashi ◽  
Yasuo Imanishi ◽  
Akimitsu Miyauchi ◽  
Naoyoshi Onoda ◽  
Takehisa Kawata ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Primary Hyperparathyroidism ◽  
Creatinine Clearance ◽  
Fibroblast Growth Factor ◽  
Time Course ◽  
Parathyroid Glands ◽  
Fibroblast Growth ◽  
Fgf 23

Objective: While the importance of fibroblast growth factor (FGF)-23 is established in phosphate-wasting disorders, little is known about the mechanisms regulating its circulating level. To investigate the role of parathyroid hormone (PTH) and calcium in FGF-23 metabolism, we examined plasma FGF-23 levels in patients with primary hyperparathyroidism (PHPT). Patients and methods: Fifty patients with PHPT and 52 controls were employed in this study. Plasma was obtained from 18 PHPT patients who underwent parathyroidectomy (PTX) on the first postoperative morning without vitamin D administration. Time-course samples were also obtained from 5 of 18 PTX patients without vitamin D analogs or calcium administration. The expression of Fgf23 on resected parathyroid glands was analyzed by reverse transcription (RT)–PCR and immunohistochemistry. Results: FGF-23 was significantly elevated in PHPT patients compared with controls. FGF-23 levels were significantly correlated positively with serum corrected calcium and intact PTH levels, and negatively with creatinine clearance and inorganic phosphate, among which creatinine clearance and corrected calcium were independently associated factors. In 18 PTX patients, postoperative FGF-23 levels were significantly decreased compared with preoperative levels. Corrected-calcium levels were significantly decreased 1 h after PTX, and this was followed by a reduction in plasma FGF-23 levels in time-course study. In addition, postoperative FGF-23 levels in 18 PTX patients were significantly correlated with corrected calcium, consistent with a role of serum calcium as one of the major regulators of FGF-23. The absence of Fgf23 expression in parathyroid glands indicated that the parathyroid glands were not major sources of circulating FGF-23. Conclusions: Serum calcium may regulate circulating FGF-23 levels in PHPT.

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