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Volumn 12, Issue 3, 2014, Pages 252-262

Hypophosphatemic rickets: Revealing novel control points for phosphate homeostasis

Author keywords

DMP1; ENPP1; Fam20c; FGF23; Furin; GALNT3; Hyperphosphatemia; Hypophosphatemia; Mineralization; Osteomalacia; Phosphate; Rickets; Klotho

Indexed keywords

FIBROBLAST GROWTH FACTOR 23; FIBROBLAST GROWTH FACTOR 23 ANTIBODY; NEUTRALIZING ANTIBODY; PHOSPHATE; UNCLASSIFIED DRUG; FIBROBLAST GROWTH FACTOR;

EID: 84906327382     PISSN: 15441873     EISSN: 15442241     Source Type: Journal    
DOI: 10.1007/s11914-014-0223-2     Document Type: Review
Times cited : (27)

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    • •• Tagliabracci VS, Engel JL, Wen J, Wiley SE, Worby CA, Kinch LN, et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science. 2012;336(6085):1150-3. This significant paper demonstrated that Fam20C belongs to a family of novel atypical protein kinases that localize within the Golgi apparatus and phosphorylate secreted proteins important for biomineralization carrying S-x-E motifs.
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    • This paper highlighted Fam20C as a novel regulator of FGF23, providing a new mechanism of FGF23 processing. FGF23 was found to be a direct substrate for phosphorylation by Fam20C, reducing O-glycosylation by GALNT3, which promotes FGF23 proteolysis by furin
    • •• Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzales DJ, Appaiah HN, et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014;111(15):5520-5. This paper highlighted Fam20C as a novel regulator of FGF23, providing a new mechanism of FGF23 processing. FGF23 was found to be a direct substrate for phosphorylation by Fam20C, reducing O-glycosylation by GALNT3, which promotes FGF23 proteolysis by furin.
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    • In response to acute kidney injury, both human and rodents showed increased circulating levels of FGF23 independent of other known stimuli of FGF23 production. The findings suggest that the rapid increases in iFGF23 and cFGF23 may be due to an additional level of FGF23 regulation, including decreased iFGF23 cleavage
    • • Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013;84(4):776-85. In response to acute kidney injury, both human and rodents showed increased circulating levels of FGF23 independent of other known stimuli of FGF23 production. The findings suggest that the rapid increases in iFGF23 and cFGF23 may be due to an additional level of FGF23 regulation, including decreased iFGF23 cleavage.
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    • Circulating alphaKlotho influences phosphate handling by controlling FGF23 production
    • This paper highlighted that cKL, a cleavage product of the FGF23 co-receptor αKlotho, stimulates bone FGF23 production resulting in hypophosphatemia, hypocalcemia, and osteomalacia. This phenotype mirrors a patient with a KL translocation characterized by a metabolic bone syndrome due to increased FGF23
    • • Smith RC, O'Bryan LM, Farrow EG, Summers LJ, Clinkenbeard EL, Roberts JL, et al. Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest. 2012;122(12):4710-5. This paper highlighted that cKL, a cleavage product of the FGF23 co-receptor αKlotho, stimulates bone FGF23 production resulting in hypophosphatemia, hypocalcemia, and osteomalacia. This phenotype mirrors a patient with a KL translocation characterized by a metabolic bone syndrome due to increased FGF23.
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    • Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23/FGFR/MAPK in vitro
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    • Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia
    • This randomized Phase1-2 trial tested an anti-FGF23 monoclonal neutralizing antibody for treatment of XLH and patients showed increased TMP/GFR, serum phosphate, and calcitriol
    • • Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124(4):1587-97. This randomized Phase1-2 trial tested an anti-FGF23 monoclonal neutralizing antibody for treatment of XLH and patients showed increased TMP/GFR, serum phosphate, and calcitriol.
    • (2014) J Clin Invest , vol.124 , Issue.4 , pp. 1587-1597
    • Carpenter, T.O.1    Imel, E.A.2    Ruppe, M.D.3    Weber, T.J.4    Klausner, M.A.5    Wooddell, M.M.6


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