Studies in a patient with tumor-induced hypophosphatemic osteomalacia

Ryan, Will G.; Gitelis, Steven; Charters, John R.

doi:10.1007/bf02555750

Cited by 12 publications

(4 citation statements)

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“…Secondary hyperparathyroidism with increased circulating levels of PTH has also been reported in Hyp and Gy mice, the murine homologs of XLH (40,41). Serum levels of PTH have been variably reported as low as well as elevated but are most frequently normal in TIO (21,42,43). The reason for the discrepancy between these clinical observations and our findings can be explained, in part, by the fact that in our animal model, deregulated overexpression would tend to raise more profoundly the circulating levels of FGF23.…”

Section: Discussionmentioning

confidence: 91%

Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

et al. 2004

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Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D(3)) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D(3) production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.

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Section: Discussionmentioning

confidence: 91%

Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

et al. 2004

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“…Additional confirmatory support for this argument is provided by the diffuse parathyroid hyperplasia observed histologically in these two groups of animals. Increased circulating levels of PTH have been reported in some patients with TIO (18,19) and in Hyp and Gy mice, the murine homologs of XLH (20). Although not described in ADHR, a trend toward higher PTH levels has been observed in patients with this disorder (1).…”

Section: Discussionmentioning

confidence: 99%

The Autosomal Dominant Hypophosphatemic Rickets R176Q Mutation in Fibroblast Growth Factor 23 Resists Proteolytic Cleavage and Enhances in Vivo Biological Potency

Xiu-juan¹,

Miao²,

Goltzman³

et al. 2003

Journal of Biological Chemistry

260

176

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Missense mutations in fibroblast growth factor 23 (FGF23) are the cause of autosomal dominant hypophosphatemic rickets (ADHR). The mutations (R176Q, R179W, and R179Q) replace Arg residues within a subtilisin-like proprotein convertase (SPC) cleavage site (RXXR motif), leading to protease resistance of FGF23. The goals of this study were to examine in vivo the biological potency of the R176Q mutant FGF23 form and to characterize alterations in homeostatic mechanisms that give rise to the phenotypic presentation of this disorder. For this, wild type and R176Q mutant FGF23 were overexpressed in the intact animals using a tumorbearing nude mouse system. At comparable circulating levels, the mutant form was more potent in inducing hypophosphatemia, in decreasing circulating concentrations of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and in causing rickets and osteomalacia in these animals compared with wild type FGF23. Parameters of calcium homeostasis were also altered, leading to secondary hyperparathyroidism and parathyroid gland hyperplasia. However, the raised circulating levels of parathyroid hormone were ineffective in normalizing the reduced 1,25(OH) 2 D 3 levels by increasing renal expression of 25(OH)D 3 -1␣-hydroxylase (Cyp40) to promote its synthesis and by decreasing that of 25(OH)D 3 -24-hydroxylase (Cyp24) to prevent its catabolism. The findings provide direct in vivo evidence that missense mutations from ADHR kindreds are gain-of-function mutations that retain and increase the protein's biological potency. Moreover, for the first time, they define a potential role for FGF23 in dissociating parathyroid hormone actions on mineral fluxes and on vitamin D metabolism at the level of the kidney.Renal phosphate wasting is associated with a number of hereditary disorders including X-linked (XLH) 1 and autosomal dominant (ADHR) forms of hypophosphatemic rickets. In addition to hypophosphatemia, patients with these two conditions exhibit decreased or inappropriately normal serum levels of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), as well as rickets and osteomalacia. Interestingly, ADHR encompasses not only the classic presentation of hypophosphatemia and rickets, but also it displays variable penetrance with delayed onset of the disease and an even more perplexing feature, spontaneous resolution of the biochemical defect (1, 2).The genes responsible for XLH and ADHR have now been identified. Through positional cloning, a gene that spans the deleted region Xp22.1 in XLH patients or is mutated in nondeletion patients with the disorder has been identified (designated PEX and subsequently PHEX, for phosphate-regulating gene with homologies to endopeptidases on the X chromosome) (3). The predicted human PHEX gene product exhibits structural similarity to a family of neutral endopeptidases involved in either activation or degradation of peptide hormones. Therefore, PHEX probably functions as a protease, and it may act by processing factor(s) involved in bone mineral metabolism. Extensive mutation analysis of XL...

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“…Reid et al reported that preoperative transiliac bone biopsy following two courses of oxytetracycline showed marked osteoid and diffuse tetracycline fluorescence, and repeated bone biopsy 3 months after the operation showed normal osteoid volume and widespread double-fluorescent labels that indicated complete healing of the osteomalacia [16]. Ryan also reported that severe osteomalacia before the operation improved 3 months after operation [17].…”

Section: Discussionmentioning

confidence: 96%