FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization

被引:245
作者
Quarles, LD [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Med, Ctr Bone & Mineral Disorders, Durham, NC 27710 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2003年 / 285卷 / 01期
关键词
phosphatonin; Hyp; X-linked hypophosphatemia; rickets; osteomalacia; hypophosphatemia;
D O I
10.1152/ajpendo.00016.2003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (ADAR) 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.
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页码:E1 / E9
页数:9
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