| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
INVITED REVIEW
Department of Medicine, Center for Bone and Mineral Disorders, Duke University Medical Center, Durham, North Carolina 27710
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.
phosphatonin; Hyp; X-linked hypophosphatemia; rickets; osteomalacia; hypophosphatemia
This article has been cited by other articles:
|
|
 |
|
  X. Zhang, D. C.Y. Yeung, M. Karpisek, D. Stejskal, Z.-G. Zhou, F. Liu, R. L.C. Wong, W.-S. Chow, A. W.K. Tso, K. S.L. Lam, et al. Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans Diabetes, May 1, 2008; 57(5): 1246 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Balazs, G. Jeha, S. K. Gunn, and L. P. Karaviti X-linked Hypophosphatemic Rickets Associated With Respiratory Failure Clinical Pediatrics, April 1, 2008; 47(3): 293 - 295. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Six, D. Septier, C. Chaussain-Miller, R. Blacher, P. DenBesten, and M. Goldberg Dentonin, a MEPE Fragment, Initiates Pulp-healing Response to Injury Journal of Dental Research, August 1, 2007; 86(8): 780 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ferrari Single Gene Mutations and Variations Affecting Bone Turnover and Strength: a Selective 2006 Update IBMS BoneKEy, December 1, 2006; 3(12): 11 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Masuda and G. Jones Promise of vitamin D analogues in the treatment of hyperproliferative conditions. Mol. Cancer Ther., April 1, 2006; 5(4): 797 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Schipani, A. Zallone, G. J. Strewler, J. W. Pike, S. Ferrari, Y. Jiang, and E. Seeman Meeting Report from the 27th Annual Meeting of the American Society for Bone and Mineral Research: September 23-27, 2005 in Nashville, Tennessee, USA IBMS BoneKEy, January 1, 2006; 3(1): 29 - 62. [Full Text] [PDF]
|
|
|
|
 |
|
 O. I. Kolek, E. R. Hines, M. D. Jones, L. K. LeSueur, M. A. Lipko, P. R. Kiela, J. F. Collins, M. R. Haussler, and F. K. Ghishan 1{alpha},25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport Am J Physiol Gastrointest Liver Physiol, December 1, 2005; 289(6): G1036 - G1042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Razzaque, R. St-Arnaud, T. Taguchi, and B. Lanske FGF-23, vitamin D and calcification: the unholy triad Nephrol. Dial. Transplant., October 1, 2005; 20(10): 2032 - 2035. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Matsumoto, O. D. Jo, R. N. J. Shih, E. J. Brochmann, S. S. Murray, V. Hong, J. Yanagawa, and N. Yanagawa Increased cathepsin D release by Hyp mouse osteoblast cells Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E123 - E132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Gutierrez, T. Isakova, E. Rhee, A. Shah, J. Holmes, G. Collerone, H. Juppner, and M. Wolf Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease J. Am. Soc. Nephrol., July 1, 2005; 16(7): 2205 - 2215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Tebben, K. R. Kalli, W. A. Cliby, L. C. Hartmann, J. P. Grande, R. J. Singh, and R. Kumar Elevated Fibroblast Growth Factor 23 in Women With Malignant Ovarian Tumors Mayo Clin. Proc., June 1, 2005; 80(6): 745 - 751. [Abstract] [PDF]
|
|
|
|
|
|
M. Ito, Y. Sakai, M. Furumoto, H. Segawa, S. Haito, S. Yamanaka, R. Nakamura, M. Kuwahata, and K.-i. Miyamoto Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1101 - E1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Tebben, R. J. Singh, B. L. Clarke, and R. Kumar Fibroblast Growth Factor 23, Parathyroid Hormone, and 1{alpha},25-Dihydroxyvitamin D in Surgically Treated Primary Hyperparathyroidism Mayo Clin. Proc., December 1, 2004; 79(12): 1508 - 1513. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Biber, S. M. Gisler, N. Hernando, C. A. Wagner, and H. Murer PDZ interactions and proximal tubular phosphate reabsorption Am J Physiol Renal Physiol, November 1, 2004; 287(5): F871 - F875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Strewler Phos, Phex and FGF: Mysteries of Phosphate Homeostasis Revealed - or Still Hidden IBMS BoneKEy, September 1, 2004; 1(9): 6 - 14. [Full Text] [PDF]
|
|
|
|
 |
|
 P. S.N. Rowe THE WRICKKENED PATHWAYS OF FGF23, MEPE AND PHEX Critical Reviews in Oral Biology & Medicine, September 1, 2004; 15(5): 264 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Sugiura and R. P. Ferraris Dietary phosphorus-responsive genes in the intestine, pyloric ceca, and kidney of rainbow trout Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R541 - R550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Segawa, I. Kaneko, S. Yamanaka, M. Ito, M. Kuwahata, Y. Inoue, S. Kato, and K.-i. Miyamoto Intestinal Na-Pi cotransporter adaptation to dietary Pi content in vitamin D receptor null mice Am J Physiol Renal Physiol, July 1, 2004; 287(1): F39 - F47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Meyer, E. Dulde, and R. A. Meyer Jr. The genomic response of the mouse kidney to low-phosphate diet is altered in X-linked hypophosphatemia Physiol Genomics, June 17, 2004; 18(1): 4 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, W. Li, C. Gao, Y. Kumagai, R.W. Blacher, and P.K. DenBesten Dentonin, a Fragment of MEPE, Enhanced Dental Pulp Stem Cell Proliferation Journal of Dental Research, June 1, 2004; 83(6): 496 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Qin, O. Baba, and W.T. Butler POST-TRANSLATIONAL MODIFICATIONS OF SIBLING PROTEINS AND THEIR ROLES IN OSTEOGENESIS AND DENTINOGENESIS Critical Reviews in Oral Biology & Medicine, May 1, 2004; 15(3): 126 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Steiglitz, M. Ayala, K. Narayanan, A. George, and D. S. Greenspan Bone Morphogenetic Protein-1/Tolloid-like Proteinases Process Dentin Matrix Protein-1 J. Biol. Chem., January 9, 2004; 279(2): 980 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ba, D. Brown, and P. A. Friedman Calcium-sensing receptor regulation of PTH-inhibitable proximal tubule phosphate transport Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1233 - F1243. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
