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Gene Review

Phex  -  phosphate regulating endopeptidase homolog...

Mus musculus

Synonyms: Gy, HPDR, HPDR1, HYP, Hyp, ...


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Disease relevance of Phex


High impact information on Phex

  • Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity [7].
  • PEX blocks MMP-2 activity on the chick chorioallantoic membrane where it disrupts angiogenesis and tumor growth [7].
  • Importantly, a naturally occurring form of PEX can be detected in vivo in conjunction with alphavbeta3 expression in tumors and during developmental retinal neovascularization [7].
  • Levels of PEX in these vascularized tissues suggest that it interacts with endothelial cell alphavbeta3 where it serves as a natural inhibitor of MMP-2 activity, thereby regulating the invasive behavior of new blood vessels [7].
  • Renal brush border membrane adaptation to phosphorus deprivation in the Hyp/Y mouse [8].
  • The mineralization-inhibiting protein osteopontin [9] abundant in the extracellular matrix of bone, and in tooth dentin and cementum, is a substrate for PHEX [10] [11]; PHEX essentially completely degrades inhibitory OPN [10].

Chemical compound and disease context of Phex


Biological context of Phex


Anatomical context of Phex


Associations of Phex with chemical compounds

  • This disorder results from mutations in the PHEX/Phex (Phosphate-regulating gene with homologies to endopeptidases on the X chromosome) gene, which is expressed in fully differentiated osteoblasts [21].
  • Phex encodes a 100- to 105-kDa glycoprotein, which is present in bones and teeth of normal mice but not Hyp animals [18].
  • Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice [3].
  • We find that PGE2 production was higher in Hyp mice than in C57/B6 mice [3].
  • To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid [3].

Regulatory relationships of Phex

  • Additional factors, associated with either osteocyte differentiation and/or extracellular matrix, are necessary for Phex deficiency to stimulate Fgf23 gene transcription in bone [22].
  • These findings suggest that Phex may control mineralization and removal of hypertrophic chondrocytes and cartilage matrix in growth plate by regulating the synthesis and deposition of certain bone matrix proteins and proteases such as MMP-9 [23].
  • These data suggested that two alternative promoters control the renal expression of Npt2a gene and both Npt2a variant transcripts are down regulated in Hyp mice [24].
  • However, the inability of PTH and hypophosphatemia to stimulate enzyme activity in a manner analogous to that in normal and phosphate-depleted mice indicates that a generalized defect of 1 alpha-hydroxylase regulation is manifest in Hyp-mice [25].
  • The present study was undertaken to evaluate the response of Hyp mice to regulators known to inhibit renal 25-hydroxyvitamin D3-1-hydroxylase (1-hydroxylase) and stimulate renal 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) [26].

Other interactions of Phex

  • We demonstrate that the underlying mutations are nested deletions which lie in the Phex-Amelx chromosomal segment conserved between man and mouse [27].
  • The authors found that Hyp mice had increased expression of the MEPE and another phosphaturic factor, Fgf23 [28].
  • Transfer of Mepe deficiency onto the Phex-deficient Hyp mouse background failed to correct hypophosphatemia and aberrant serum 1,25(OH)(2)D(3) levels [28].
  • We show that the most likely gene order in the distal portion of the mouse X chromosome is Pgk-1-DXSmh43-Hyp-Cbx-rs1-Amg, from proximal to distal [29].
  • We have established a Mus spretus/Mus musculus domesticus interspecific backcross segregating for two X-linked mutant genes, Ta and Hyp, using in vitro fertilization [29].
  • The mineralization-inhibiting protein osteopontin [9] abundant in the extracellular matrix of bone, and in tooth dentin and cementum, is a substrate for PHEX [10] [11]; PHEX essentially completely degrades inhibitory OPN [10].  PHEX also degrades the ASARM peptide from MEPE [30] and OPN [31].

Analytical, diagnostic and therapeutic context of Phex


  1. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Sabbagh, Y., Carpenter, T.O., Demay, M.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Spermine synthesis is required for normal viability, growth, and fertility in the mouse. Wang, X., Ikeguchi, Y., McCloskey, D.E., Nelson, P., Pegg, A.E. J. Biol. Chem. (2004) [Pubmed]
  3. Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro. Syal, A., Schiavi, S., Chakravarty, S., Dwarakanath, V., Quigley, R., Baum, M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  4. Effects of altered diet on serum levels of 1,25-dihydroxyvitamin D and parathyroid hormone in X-linked hypophosphatemic (Hyp and Gy) mice. Meyer, R.A., Meyer, M.H., Morgan, P.L. Bone (1996) [Pubmed]
  5. Osteocalcin production in primary osteoblast cultures derived from normal and Hyp mice. Carpenter, T.O., Moltz, K.C., Ellis, B., Andreoli, M., McCarthy, T.L., Centrella, M., Bryan, D., Gundberg, C.M. Endocrinology (1998) [Pubmed]
  6. Early lethality in Hyp mice with targeted deletion of Pth gene. Bai, X., Miao, D., Goltzman, D., Karaplis, A.C. Endocrinology (2007) [Pubmed]
  7. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Brooks, P.C., Silletti, S., von Schalscha, T.L., Friedlander, M., Cheresh, D.A. Cell (1998) [Pubmed]
  8. Renal brush border membrane adaptation to phosphorus deprivation in the Hyp/Y mouse. Tenenhouse, H.S., Scriver, C.R. Nature (1979) [Pubmed]
  9. Osteopontin. Sodek, J., Ganss, B., McKee, M.D. Crit. Rev. Oral. Biol. Med. (2000) [Pubmed]
  10. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. Barros, N.M., Hoac, B., Neves, R.L., Addison, W.N., Assis, D.M., Murshed, M., Carmona, A.K., McKee, M.D. J. Bone. Miner. Res. (2013) [Pubmed]
  11. Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. McKee, M.D., Hoac, B., Addison, W.N., Barros, N.M., Millán, J.L., Chaussain, C. Periodontol. 2000. (2013) [Pubmed]
  12. Partial deletion of both the spermine synthase gene and the Pex gene in the X-linked hypophosphatemic, gyro (Gy) mouse. Meyer, R.A., Henley, C.M., Meyer, M.H., Morgan, P.L., McDonald, A.G., Mills, C., Price, D.K. Genomics (1998) [Pubmed]
  13. Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia. Baum, M., Syal, A., Quigley, R., Seikaly, M. Pediatr. Nephrol. (2006) [Pubmed]
  14. Abnormal vitamin D metabolism in the X-linked hypophosphatemic mouse. Meyer, R.A., Gray, R.W., Meyer, M.H. Endocrinology (1980) [Pubmed]
  15. Effect of the Hyp mutation and diet-induced hyperparathyroidism on renal parathyroid hormone- and forskolin-stimulated adenosine 3',5'-monophosphate production and brush border membrane phosphate transport. Tenenhouse, H.S., Veksler, A. Endocrinology (1986) [Pubmed]
  16. Effects of magnesium and lactose supplementation on bone metabolism in the X-linked hypophosphatemic mouse. Marie, P.J., Travers, R. Metab. Clin. Exp. (1983) [Pubmed]
  17. An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets. Carpinelli, M.R., Wicks, I.P., Sims, N.A., O'Donnell, K., Hanzinikolas, K., Burt, R., Foote, S.J., Bahlo, M., Alexander, W.S., Hilton, D.J. Am. J. Pathol. (2002) [Pubmed]
  18. Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers. Ruchon, A.F., Tenenhouse, H.S., Marcinkiewicz, M., Siegfried, G., Aubin, J.E., DesGroseillers, L., Crine, P., Boileau, G. J. Bone Miner. Res. (2000) [Pubmed]
  19. Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. Thompson, D.L., Sabbagh, Y., Tenenhouse, H.S., Roche, P.C., Drezner, M.K., Salisbury, J.L., Grande, J.P., Poeschla, E.M., Kumar, R. J. Bone Miner. Res. (2002) [Pubmed]
  20. Overexpression of Phex in osteoblasts fails to rescue the Hyp mouse phenotype. Liu, S., Guo, R., Tu, Q., Quarles, L.D. J. Biol. Chem. (2002) [Pubmed]
  21. Downregulation of osteoblast Phex expression by PTH. Alos, N., Ecarot, B. Bone (2005) [Pubmed]
  22. Pathogenic role of Fgf23 in Hyp mice. Liu, S., Zhou, J., Tang, W., Jiang, X., Rowe, D.W., Quarles, L.D. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  23. Cartilage abnormalities are associated with abnormal Phex expression and with altered matrix protein and MMP-9 localization in Hyp mice. Miao, D., Bai, X., Panda, D.K., Karaplis, A.C., Goltzman, D., McKee, M.D. Bone (2004) [Pubmed]
  24. Alternative promoters and renal cell-specific regulation of the mouse type IIa sodium-dependent phosphate cotransporter gene. Yamamoto, H., Tani, Y., Kobayashi, K., Taketani, Y., Sato, T., Arai, H., Morita, K., Miyamoto, K., Pike, J.W., Kato, S., Takeda, E. Biochim. Biophys. Acta (2005) [Pubmed]
  25. Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism. Nesbitt, T., Drezner, M.K., Lobaugh, B. J. Clin. Invest. (1986) [Pubmed]
  26. Effect of the X-linked Hyp mutation and vitamin D status on induction of renal 25-hydroxyvitamin D3-24-hydroxylase. Tenenhouse, H.S., Jones, G. Endocrinology (1987) [Pubmed]
  27. Mouse mutants carrying deletions that remove the genes mutated in Coffin-Lowry syndrome and lactic acidosis. Blair, H.J., Gormally, E., Uwechue, I.C., Boyd, Y. Hum. Mol. Genet. (1998) [Pubmed]
  28. Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia. Liu, S., Brown, T.A., Zhou, J., Xiao, Z.S., Awad, H., Guilak, F., Quarles, L.D. J. Am. Soc. Nephrol. (2005) [Pubmed]
  29. Determination of a molecular map position for Hyp using a new interspecific backcross produced by in vitro fertilization. Kay, G., Thakker, R.V., Rastan, S. Genomics (1991) [Pubmed]
  30. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. Addison, W.N., Nakano, Y., Loisel, T., Crine, P., McKee, M.D. J. Bone. Miner. Res. (2008) [Pubmed]
  31. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. Addison, W.N., Masica, D.L., Gray, J.J., McKee, M.D. J. Bone. Miner. Res. (2010) [Pubmed]
  32. Analysis of recombinant Phex: an endopeptidase in search of a substrate. Guo, R., Liu, S., Spurney, R.F., Quarles, L.D. Am. J. Physiol. Endocrinol. Metab. (2001) [Pubmed]
  33. Skeletal casein kinase activity defect in the HYP mouse. Rifas, L., Cheng, S., Halstead, L.R., Gupta, A., Hruska, K.A., Avioli, L.V. Calcif. Tissue Int. (1997) [Pubmed]
  34. Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts. Guo, R., Quarles, L.D. J. Bone Miner. Res. (1997) [Pubmed]
  35. Serum insulin-like growth factor binding protein-3 in the hypophosphatemic mouse: decreased activity and abnormal modulation by dietary phosphate. Moriwake, T., Abribat, T., Brazeau, P., Ecarot, B. J. Bone Miner. Res. (1995) [Pubmed]
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