{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:59:57Z","timestamp":1793167197451,"version":"4.5.0"},"reference-count":81,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2003,7]]},"abstract":"<jats:p> 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 \u201cphosphatonins,\u201d 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. <\/jats:p>","DOI":"10.1152\/ajpendo.00016.2003","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T19:52:17Z","timestamp":1425412337000},"page":"E1-E9","source":"Crossref","is-referenced-by-count":278,"title":["FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal  mineralization"],"prefix":"10.1152","volume":"285","author":[{"given":"L. Darryl","family":"Quarles","sequence":"first","affiliation":[{"name":"Department of Medicine, Center for Bone and Mineral Disorders, Duke  University Medical Center, Durham, North Carolina 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","unstructured":"Allen HC,  Whybro A, Barker ME, Estell R, and Blumsohn A. Endocrine response to  escalating-dose phosphate supplementation in men: is FGF-23 phosphatonin?  J Bone Miner Res 17:  S159, 2002."},{"key":"REF2","doi-asserted-by":"publisher","DOI":"10.1038\/81664"},{"key":"REF3","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2001.6553"},{"key":"REF4","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0113"},{"key":"REF5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119276"},{"key":"REF6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.9.5372"},{"key":"REF7","unstructured":"Berndt TJ,  Vassiliadis J, Reczek D, Schiavi SC, and Kumar R. Effect of the acute  infusion of frizzled related protein 4 (FRP-4), a protein highly expressed in  tumors associated with osteomalacia, on phosphate excretion in vivo.  J Bone Miner Res 17:  S158, 2002."},{"key":"REF8","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10075"},{"key":"REF9","doi-asserted-by":"publisher","DOI":"10.1042\/bj3550707"},{"key":"REF10","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5084"},{"key":"REF11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa013444"},{"key":"REF12","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(64)90085-3"},{"key":"REF13","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2001.00781.x"},{"key":"REF14","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64468-9"},{"key":"REF15","doi-asserted-by":"crossref","unstructured":"Collins MT,  Chebli C, Jones J, Kushner H, Consugar M, Rinaldo P, Wientroub S, Bianco P,  and Robey PG. Renal phosphate wasting in fibrous dysplasia of bone is part  of a generalized renal tubular dysfunction similar to that seen in  tumor-induced osteomalacia. J Bone Miner Res 5: 806\u2013813,  2001.","DOI":"10.1359\/jbmr.2001.16.5.806"},{"key":"REF16","doi-asserted-by":"publisher","DOI":"10.1038\/ng0496-390"},{"key":"REF17","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2002.17.6.1102"},{"key":"REF18","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81069-7"},{"key":"REF19","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0421"},{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00135.2002"},{"key":"REF21","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650070213"},{"key":"REF22","doi-asserted-by":"publisher","DOI":"10.1210\/endo-123-2-768"},{"key":"REF23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119809"},{"key":"REF24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.25.15262"},{"key":"REF25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203250200"},{"key":"REF26","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6153"},{"key":"REF27","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(00)00302-1"},{"key":"REF28","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.281.4.E837"},{"key":"REF29","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1997.12.7.1009"},{"key":"REF30","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02125-3"},{"key":"REF31","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5477.265"},{"key":"REF32","unstructured":"Holm IA, Huang  X, and Kunkel LM. Mutational analysis of the PHEX gene in patients with  X-linked hypophosphatemic rickets. Am J Hum Genet 60: 790\u2013797,  1997."},{"key":"REF33","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00285-9"},{"key":"REF34","doi-asserted-by":"crossref","unstructured":"Kruse K,  Woelfel D, Strom TM, and Storm TM. Loss of renal phosphate wasting in a  child with autosomal dominant hypophosphatemic rickets caused by a FGF23  mutation. Horm Res 55:  305\u2013308, 2001.","DOI":"10.1159\/000050018"},{"key":"REF35","unstructured":"Kumar R.  New insights into phosphate homeostasis: fibroblast growth factor 23 and  frizzled-related protein-4 are phosphaturic factors derived from tumors  associated with osteomalacia. Curr Opin Nephrol  Hypertens 11:  577\u2013553, 2002."},{"key":"REF36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103433200"},{"key":"REF37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.14.6353"},{"key":"REF38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.22.13729"},{"key":"REF39","doi-asserted-by":"crossref","unstructured":"Liu S, Guo R,  Tu Q, and Quarles LD. Overexpression of PHEX in osteoblasts fails to  rescue the Hyp mouse phenotype. J Biol Chem 275: 3689\u20133697,  2002.","DOI":"10.1074\/jbc.M107707200"},{"key":"REF40","doi-asserted-by":"publisher","DOI":"10.1080\/03008200290000556"},{"key":"REF41","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1997.5169"},{"key":"REF42","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650040407"},{"key":"REF43","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650040411"},{"key":"REF44","doi-asserted-by":"publisher","DOI":"10.1210\/endo.142.2.7976"},{"key":"REF45","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00261-7"},{"key":"REF46","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2000.15.8.1451"},{"key":"REF47","doi-asserted-by":"publisher","DOI":"10.1042\/bj3270625"},{"key":"REF48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115735"},{"key":"REF49","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1999.14.12.2027"},{"key":"REF50","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(00)00418-X"},{"key":"REF51","doi-asserted-by":"crossref","unstructured":"Nurnberg P,  Thiele H, Chandler D, Hohne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K,  Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F,  Mundlos S, Braun HS, Laing N, and Tinschert S. Heterozygous mutations in  ANKH, the human ortholog of the mouse progressive ankylosis gene, result in  craniometaphyseal dysplasia. Nat Genet 28: 37\u201341,  2001.","DOI":"10.1038\/ng0501-37"},{"key":"REF52","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3492"},{"key":"REF53","doi-asserted-by":"publisher","DOI":"10.1101\/gad.990702"},{"key":"REF54","doi-asserted-by":"crossref","unstructured":"Palmer G,  Guicheux J, Bonjour JP, and Caverzasio J. Transforming growth factor-beta  stimulates inorganic phosphate transport and expression of the type III  phosphate transporter Glvr-1 in chondrogenic ATDC5 cells.  Endocrinology 141:  2236\u20132243, 2001.","DOI":"10.1210\/en.141.6.2236"},{"key":"REF55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003622200"},{"key":"REF56","doi-asserted-by":"publisher","DOI":"10.1677\/erc.0.0070165"},{"key":"REF57","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.2.7302"},{"key":"REF58","unstructured":"Rasmussen H and  Anast C. Familial hypophosphatemic rickets and vitamin D-dependent  rickets. In: The Metabolic Basis of Inherited Disease,  edited by Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, and Brown  MS. New York: McGraw Hill, 1983, p.  1743\u20131773."},{"key":"REF59","doi-asserted-by":"publisher","DOI":"10.1007\/s002239900331"},{"key":"REF60","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6235"},{"key":"REF61","doi-asserted-by":"publisher","DOI":"10.1177\/002215549804600405"},{"key":"REF62","unstructured":"Ruchon AF,  Tenenhouse HS, Marcinkiewicz M, Siegfried G, Aubin JE, DesGroseillers L, Crine  P, and Boileau G. Developmental expression and tissue distribution of PHEX  protein: effect of the Hyp mutation and relationship to bone markers.  J Bone Miner Res 8:  1440\u20131450, 2000."},{"key":"REF63","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207872200"},{"key":"REF64","unstructured":"Shimada T,  Kakitani M, Hasegawa H, Yamazaki Y, Ohguma A, Takeuchi Y, Fujita T, Fukumoto  S, Tomizuka K, and Yamashita T. Targeted ablation of FGF-23 causes  hyperphosphatemia, increased 1,25-dihydroxyvitamin D levels and severe growth  retardation (Abstract). J Bone Miner Res 17: S168,  2002."},{"key":"REF65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.101545198"},{"key":"REF66","doi-asserted-by":"publisher","DOI":"10.1210\/endo.143.8.8795"},{"key":"REF67","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008511200"},{"key":"REF68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111154898"},{"key":"REF69","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.2.165"},{"key":"REF70","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-130"},{"key":"REF71","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2002.17.2.311"},{"key":"REF72","doi-asserted-by":"publisher","DOI":"10.1007\/0-306-46826-3_25"},{"key":"REF73","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(98)00321-0"},{"key":"REF74","unstructured":"Weber T, Liu S,  Indridason O, and Quarles LD. Serum FGF-23 levels in normal and  disordered phosphorus homeostasis. In press."},{"key":"REF75","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.2.7408"},{"key":"REF76","unstructured":"Whyte MP,  Schranck FW, and Armamento-Villareal R. X-linked hypophosphatemia: a  search for gender, race, anticipation, or parent of origin effects on disease  expression in children. J Clin Endocrinol Metab 81: 4075\u20134080,  1996."},{"key":"REF77","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199105000-00006"},{"key":"REF78","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1998.275.4.E700"},{"key":"REF79","unstructured":"Yamamoto T,  Miyamoto KI, Ozono K, Taketani Y, Katai K, Miyauchi A, Shima M, Yoshikawa H,  Yoh K, Takeda E, and Okada S. Hypophosphatemic rickets accompanying  McCune-Albright syndrome: evidence that a humoral factor causes  hypophosphatemia. J Bone Miner Metab 5: 287\u2013295,  2001."},{"key":"REF80","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202527200"},{"key":"REF81","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021105"}],"container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpendo.00016.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T18:16:12Z","timestamp":1567966572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpendo.00016.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,7]]},"references-count":81,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2003,7]]}},"alternative-id":["10.1152\/ajpendo.00016.2003"],"URL":"https:\/\/doi.org\/10.1152\/ajpendo.00016.2003","relation":{},"ISSN":["0193-1849","1522-1555"],"issn-type":[{"value":"0193-1849","type":"print"},{"value":"1522-1555","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,7]]}}}