title: FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization.
abstract: There is evidence for a hormone/enzyme/extracellular matrix protein cascade involving fibroblastic growth factor 23 (FGF23), a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), and a matrix extracellular phosphoglycoprotein (MEPE) that regulates systemic phosphate homeostasis and mineralization. Genetic studies of autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH) identified the phosphaturic hormone FGF23 and the membrane metalloprotease PHEX, and investigations of tumor-induced osteomalacia (TIO) discovered the extracellular matrix protein MEPE. Similarities between ADHR, XLH, and TIO suggest a model to explain the common pathogenesis of renal phosphate wasting and defective mineralization in these disorders. In this model, increments in FGF23 and MEPE, respectively, cause renal phosphate wasting and intrinsic mineralization abnormalities. FGF23 elevations in ADHR are due to mutations of FGF23 that block its degradation, in XLH from indirect actions of inactivating mutations of PHEX to modify the expression and/or degradation of FGF23 and MEPE, and in TIO because of increased production of FGF23 and MEPE. Although this model is attractive, several aspects need to be validated. First, the enzymes responsible for metabolizing FGF23 and MEPE need to be established. Second, the physiologically relevant PHEX substrates and the mechanisms whereby PHEX controls FGF23 and MEPE metabolism need to be elucidated. Finally, additional studies are required to establish the molecular mechanisms of FGF23 and MEPE actions on kidney and bone, as well as to confirm the role of these and other potential "phosphatonins," such as frizzled related protein-4, in the pathogenesis of the renal and skeletal phenotypes in XLH and TIO. Unraveling the components of this hormone/enzyme/extracellular matrix pathway will not only lead to a better understanding of phosphate homeostasis and mineralization but may also improve the diagnosis and treatment of hypo- and hyperphosphatemic disorders.
authors.affiliation: Department of Medicine, Center for Bone and Mineral Disorders, Duke University Medical Center, Durham, North Carolina 27710, USA. Quarl001@mc.duke.edu
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology*; D016326:Extracellular Matrix Proteins; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010018:Osteomalacia / Q000235:genetics; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010710:Phosphates / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; D006023:Glycoproteins; C486579:MEPE protein, human; D010710:Phosphates; D010750:Phosphoproteins; D011506:Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human