Evidence for Abnormal Translational Regulation of Renal 25-Hydroxyvitamin D-1α-Hydroxylase Activity in the<i>Hyp</i>-Mouse

Yuan, Baozhi; Xing, Yina; Horst, R. L.; Drezner, Marc K.

doi:10.1210/en.2004-0192

Cited by 28 publications

(46 citation statements)

References 53 publications

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“…/Hyp mice; n Ն 5), consistent with the previously reported posttranscriptional defect that underlies the abnormal vitamin D metabolism in Hyp mice. 28 Unexpected, we observed an approximately two-fold increase in both circulating FGF23 level and FGF23 message level in bone of combined FGFR3 Ϫ/Ϫ /Hyp mice above the already elevated levels in Hyp mice (Table 1, Figure 4A). The FGFR3-dependent regulation of FGF23 levels was observed only in the Hyp mouse background, and loss of FGFR3 had no effect on FGF23 levels in mice lacking the Phex mutation.…”

Section: Regulation In Hyp Micementioning

confidence: 66%

FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23

Liu

Vierthaler²,

Tang³

et al. 2008

Journal of the American Society of Nephrology

129

104

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Fibroblast growth factor 23 (FGF23) is a phosphaturic factor that suppresses both sodium-dependent phosphate transport and production of 1,25-dihydroxyvitamin D [1,25(OH) 2 D] in the proximal tubule. In vitro studies suggest that FGFR3 is the physiologically relevant receptor for FGF23 in the kidney, but this has not been established in vivo. Here, immunohistochemical analysis of the mouse kidney revealed that the proximal tubule expresses FGF receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4. Compared with wild-type mice, Hyp mice, which have elevated circulating levels of FGF23, exhibited low levels of serum phosphate and 1,25(OH) 2 D, reduced expression of the sodium-dependent phosphate transporter NPT2a in the proximal tubules, and low bone mineral density as a result of osteomalacia. In contrast, neither the serum phosphate nor 1,25(OH) 2 D levels were altered in FGFR3-null mice. For examination of the role of FGFR3 in mediating the effects of FGF23, Hyp mice were crossed with FGFR3-null mice; interestingly, this failed to correct the aforementioned metabolic abnormalities of Hyp mice. Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mice. Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the kidney localization of FGFR1 was investigated. FGFR1 co-localized with Klotho, the co-factor required for FGF23-dependent FGFR activation, in the distal tubule. In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the proximal tubule, and co-localization of FGFR1 and Klotho suggests that the distal tubule may be an effector site of FGF23. Fibroblast growth factor 23 (FGF23), a phosphaturic factor predominantly produced by osteocytes in bone, 1 causes hypophosphatemia, suppression of 1,25-dihydroxyvitamin D [1,25(OH) 2 D] production, and rickets/osteomalacia. 1-4 Excess FGF23 mediates renal phosphate wasting in hereditary human hypophosphatemic disorders, including autosomal dominant hypophosphatemic rickets, 5,6 Xlinked hypophosphatemia, 7,8 and autosomal recessive hypophosphatemic rickets. 9,10 Elevated FGF23 also mediates hypophosphatemia in several acquired disorders, including tumor-induced osteomalacia, 11 McCune-Albright syndrome, and polyostotic fibrous dysplasia. 12 FGF23 inhibits the sodium-dependent phosphate transporter and CYP27B1 activity in the proximal tubule of the kidney, leading to phosphaturia and reduced production of 1,25(OH) 2 D. 2,11,13,14 FGF23 binds to and activates FGF receptors (FGFR) 1c, 3c, and 4 in cell lines that coexpress Klotho, a transmembrane protein co-factor that determines the tissue specificity of FGF23. 15,16 FGF23 has been shown to inhibit directly phosphate transport and to suppress 1␣-hydroxylase gene expression in isolated proximal tubules and/or proximal tubule-derived cell lines in

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Section: Regulation In Hyp Micementioning

confidence: 66%

FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23

Liu

Vierthaler²,

Tang³

et al. 2008

Journal of the American Society of Nephrology

129

104

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“…In previous studies, we established that hyp-mice manifest aberrant regulation of vitamin D metabolism, resulting from a unique abnormality in 25-hydroxyvitamin D-1α-hydroxylase [25(OH)D-1α-hydroxylase] translational activity (22). To ascertain whether Phex deletion resulted in a similar defect, we investigated Pi-and parathyroid hormone-mediated (PTH-mediated) vitamin D metabolism in both knockout mice.…”

Section: Figurementioning

confidence: 99%

“…Serum Pi levels were measured using a Phosphorus Liqui-UV kit from Stanbio Laboratory, as described previously (22). Serum calcium levels were assayed using a Calcium Liquicolor kit from Stanbio Laboratory following the protocol of the manufacturer.…”

Section: Biochemical Measurementsmentioning

confidence: 99%

Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia

Yuan¹,

Takaiwa²,

Clemens³

et al. 2008

J. Clin. Invest.

Self Cite

101

115

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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-Phex Δflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-Phex Δflox/y ). Serum phosphorus levels in Cre-Phex Δflox/y , OC-Cre-Phex Δflox/y , and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-Phex Δflox/y , OC-Cre-Phex Δflox/y , and hypmice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in CrePhex Δflox/y and OC-Cre-Phex Δflox/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-Phex Δflox/y , OC-Cre-Phex Δflox/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.

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“…Hyp mice have abnormal 1-␣-hydroxylase responses to PTH infusion and to low-phosphate diet (65-67). Yuan et al (67) demonstrated a normal increase in 1-␣-hydroxylase mRNA in Hyp mice after PTH infusion, similar to that seen in normal mice after PTH infusion. In their study, this was not accompanied by an increase in renal 1-␣-hydroxylase enzyme, suggesting a posttranscriptional or posttranslational modification of the 1-␣-hydroxylase response to PTH and low-phosphate diet.…”

Section: Vitamin Dmentioning

confidence: 72%

“…However, administration of calcitonin, another known stimulus to calcitriol production, results in normal stimulation of Hyp mouse 1-␣-hydroxylase (67,70) and normal stimulation of serum calcitriol in patients with XLH (71). This discrepancy suggests that the defect underlying the abnormal calcitriol production in XLH, as well as in ADHR and TIO, is incomplete and may be overcome with the appropriate stimulation of a PTH-independent pathway.…”

Section: Vitamin Dmentioning

confidence: 99%

Fibroblast Growth Factor 23

Imel¹,

Econs²

2005

Journal of the American Society of Nephrology

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A lthough phosphate is important in skeletal mineralization, energy metabolism, and multiple enzymatic processes, little has been understood about the regulation of phosphate in health and disease until recently. Genetic and acquired disorders of phosphate homeostasis have begun to reveal important mechanisms for the regulation of phosphate metabolism. Candidate phosphate-regulating hormones ("phosphatonins") have been discovered, and their actions and interactions continue to be elucidated in an exciting area of ongoing clinical and basic research. Autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), and fibrous dysplasia (FD) have similar phenotypes of hypophosphatemia, urinary phosphate wasting as measured by a low tubular maximum reabsorption of phosphate per deciliter of glomerular filtrate (TmP/GFR), osteomalacia, and rickets. The phenotypic similarities suggest a common metabolic pathophysiology. In addition, recent evidence concerning tumoral calcinosis, which results in hyperphosphatemia, inappropriately elevated calcitriol concentrations, and soft tissue calcifications and can be considered the phenotypic "converse" of the phosphate wasting disorders, indicates that this disorder may result from perturbations of some of the same metabolic pathways. Fibroblast growth factor 23 (FGF23) is a recently discovered, novel, secreted protein hormone involved in the pathogenesis of these disorders. This review focuses on the relationship of FGF23 to various disorders of phosphate homeostasis and its potential regulation and function in normal physiology. Hypophosphatemic DisordersADHR ADHR, initially described by Bianchine et al. (1), is characterized by renal phosphate wasting, hypophosphatemia, low or inappropriately normal calcitriol concentrations, and osteomalacia. Econs and McEnery (2) described a large ADHR kindred. Affected patients presented either in childhood with hypophosphatemia and rickets, which resulted in lower extremity deformities, or after puberty with hypophosphatemic osteomalacia, manifesting in weakness, fatigue, bone pain, and fractures. Patients with adult onset of symptoms clinically resemble TIO, but the disease is not a paraneoplastic process. To date, delayed onset of clinically evident disease has been observed only in female individuals. ADHR also exhibits incomplete penetrance, and, in some cases, the clinical and biochemical phenotype spontaneously resolved in patients who were previously documented to have hypophosphatemic rickets (2).The ADHR consortium used the positional cloning approach to identify the gene responsible for ADHR, FGF23 (3). ADHR results from mutations in either arginine 176 or arginine 179 in FGF23. These arginines make up an RXXR cleavage site, and mutations in either of these arginines protect the protein from degradation, potentially increasing the circulating concentration of FGF23 and, thereby, leading to the disease phenotype (4 -6). FGF23 is a 251-amino acid protein in the FGF fa...

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Evidence for Abnormal Translational Regulation of Renal 25-Hydroxyvitamin D-1α-Hydroxylase Activity in theHyp-Mouse

Cited by 28 publications

References 53 publications

FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23

FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23

Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia

Fibroblast Growth Factor 23

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