Phosphate wasting and fibroblast growth factor-23

Nanes, Mark S.

doi:10.1097/01.med.0000436189.80104.80

Cited by 9 publications

(11 citation statements)

References 40 publications

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“…First, the unraveling of novel molecular mechanisms regulating phosphate bone-mineral metabolism and the discovery of key genes involved in several inherited bone mineral loss disorders. A group of these genes are responsible for several inherited diseases causing hypophosphatemic rickets [35]. These diseases are unified further by dis-regulated FGF23 expression and profound changes in energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

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ContextPHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders.DesignSubcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks.ResultsSPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice.ConclusionsASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes.

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Section: Introductionmentioning

confidence: 99%

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

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“…1 Perhaps the least common cause of osteomalacia is that due to a neoplasm, so-called tumor-induced osteomalacia (TIO). The most common causes include vitamin D deficiency, intestinal malabsorption, and chronic renal failure.…”

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confidence: 99%

A Novel Chromogenic In Situ Hybridization Assay for FGF23 mRNA in Phosphaturic Mesenchymal Tumors

Carter

Caron

Doğan

et al. 2015

American Journal of Surgical Pathology

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Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT) are very rare tumors of bone and soft tissues. Most patients with PMT have long-standing osteomalacia secondary to production of fibroblast growth factor 23 (FGF23), a hormone that inhibits phosphate reuptake within the renal proximal tubule. Previously, we have reported the detection of FGF23 mRNA in PMT by reverse transcription polymerase chain reaction (PCR); however, the low specificity and risk for nontumoral tissue contamination inherent in PCR-based methodology limit its clinical utility. We evaluated RNAscope as a semiquantitative method of in situ FGF23 mRNA detection in the diagnosis of PMT. Twenty-five PMTs (median 52 y, range 5 to 73 y) occurred in patients with tumor-induced osteomalacia (TIO), manifesting as masses (mean 3.9 cm, range 1.4 to 12 cm) in various bones and soft tissues. FGF23 mRNA was positive in 96% (22/23) informative cases of PMT: 16 cases scored 3+; 5 scored as 2+; 1 scored as 1+. Among these cases, FGF23 mRNA was detected in 3 malignant PMTs along with their metastases. Forty control cases included aneurysmal bone cyst (N=4), chondromyxoid fibroma (N=8), high-grade osteosarcomas (N=8), and (nonfamilial) tumoral calcinosis, as well as miscellaneous cartilage-forming tumors or osteoid-forming tumors and soft tissue tumors. All control cases were negative for FGF23 mRNA in the lesional cells. One aneurysmal bone cyst had rare FGF23 mRNA-expressing osteocytes clustered around remodeled bone. One ovarian serous carcinoma in a patient with disseminated disease, elevated serum FGF23, and TIO was negative for FGF23 mRNA in the neoplastic cells. We conclude that RNAscope is a highly sensitive and specific, semiquantitative in situ hybridization method of FGF23 mRNA detection applicable to formalin-fixed, paraffin-embedded tissues. Detection of FGF23 expression is a valuable diagnostic adjunct, especially in patients with occult TIO. Compared with reverse transcription PCR, this method preserves tissue morphology and reduces "false positives" related to detection of endogenous FGF23 mRNA expression by osteocytes.

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“…22 Treatment for ADHR comprises of phosphate and calcitriol supplementation to improve height, reduce bone pain, minimize skeletal deformities, and enhance mineralization of bones. 23…”

Section: Types Of Hypophosphatemic Rickets X-linked Hypophosphatemic mentioning

confidence: 99%

Genetics of Refractory Rickets: Identification of Novel PHEX Mutations in Indian Patients and a Literature Update

et al. 2018

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Refractory rickets is a genetic disorder that cannot be treated by vitamin D supplementation and adequate dietary calcium and phosphorus. Hereditary hypophosphatemic rickets is one of the major forms of refractory rickets in Indian children and caused due to mutations in the , , , , and genes. This is the first study in India on a large number of patients reporting on mutational screening of the gene. Direct sequencing in 37 patients with refractory rickets revealed eight mutations in 13 patients of which 1 was nonsense, 2 were deletions, 1 was a deletion-insertion, and 4 were missense mutations. Of these mutations, four (c.566_567 delAG, c.651_654delACAT, c.1337delinsAATAA, and c.2048T > A) were novel mutations. This article discusses the mutations in Indian patients, collates information on the genetic causes of refractory rickets, and emphasizes the significance of genetic testing for precise diagnosis, timely treatment, and management of the condition, especially in developing countries.

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Phosphate wasting and fibroblast growth factor-23

Abstract: Derangements in FGF-23 production, half-life or downstream response are responsible for several disorders of phosphate wasting, rickets and oncogenic osteomalacia. Very high levels of FGF-23 in renal failure are an independent risk for cardiovascular disease.

Cited by 9 publications

References 40 publications

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

A Novel Chromogenic In Situ Hybridization Assay for FGF23 mRNA in Phosphaturic Mesenchymal Tumors

Genetics of Refractory Rickets: Identification of Novel PHEX Mutations in Indian Patients and a Literature Update

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