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PHEX, FGF23, DMP1 and beyond

Strom, Tim Ma,b; Jüppner, Haraldc,d

Current Opinion in Nephrology and Hypertension: July 2008 - Volume 17 - Issue 4 - p 357–362
doi: 10.1097/MNH.0b013e3282fd6e5b
Mineral metabolism: Edited by Justin Silver and David A. Bushinsky

Purpose of review We aim to review the biological properties of novel molecules that are members of a kidney–bone axis involved in the regulation of phosphate homeostasis. In addition, we describe how an improved knowledge of the mechanisms leading to changes in renal phosphate handling may lead to the development of novel therapeutic approaches.

Recent findings As yet, eight genes involved in the regulation of phosphate homeostasis have been identified through genetic studies. A key protein in this regulatory pathway is FGF23, which is made by osteocytes and activates renal KLOTHO/FGFR1 receptor heterodimers to inhibit renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Gain-of-function mutations in FGF23, which render the hormone resistant to proteolytic cleavage, lead to increased phosphaturic activity. Furthermore, inactivating mutations in DMP1 and PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion. In contrast, loss-of-function mutations in FGF23 and KLOTHO, and abnormal O-glycosylation of FGF23 because of GALNT3 mutations, lead to diminished phosphate excretion. Extremely high levels of FGF23 are observed in chronic renal failure, which may contribute to the development of renal osteodystrophy.

Summary The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis, although it is not yet completely understood how these proteins interact, and additional proteins are likely to contribute to these regulatory events.

aInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany

bInstitute of Human Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany

cEndocrine Unit, USA

dPediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Correspondence to Tim M. Strom, MD, Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany Tel: +49 89 3187 3296; fax: +49 89 3187 3297; e-mail:

© 2008 Lippincott Williams & Wilkins, Inc.