|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 5, 3686-3697, February 1, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Department of Medicine, Duke University Medical Center,
Durham, North Carolina 27710
Inactivating mutations of Phex, a
phosphate-regulating endopeptidase, cause hypophosphatemia and impaired
mineralization in X-linked hypophosphatemia (XLH) and its mouse
homologue, Hyp. Because Phex is predominantly
expressed in bone and cultured osteoblasts from Hyp mice
display an apparent intrinsic mineralization defect, it is thought that
reduced expression of Phex in mature osteoblasts is the
primary cause of XLH. To test this hypothesis, we studied both targeted
expression of Phex to osteoblasts in vivo under the control of the mouse osteocalcin (OG2) promoter
and retroviral mediated overexpression of Phex in
Hyp-derived osteoblasts (TMOb-Hyp) in
vitro. Targeted overexpression of Phex to osteoblasts
of OG2 Phex transgenic Hyp mice normalized
Phex endopeptidase activity in bone but failed to correct
the hypophosphatemia, rickets, or osteomalacia. OG2 Phex
transgenic Hyp mice did exhibit a small, but significant,
increase in bone mineral density and dry ashed weight, suggesting a
partial mineralization effect from restoration of Phex
function in mature osteoblasts. Similarly, retroviral mediated
overexpression of Phex in TMOb-Hyp osteoblasts
restored Phex mRNA levels, protein expression, and
endopeptidase activity but failed to correct their intrinsic
mineralization defect. In addition, we failed to detect the
Phex substrate FGF-23 in osteoblasts. Taken together, these
in vivo and in vitro data indicate that expression of Phex in osteoblasts is not sufficient to
rescue the Hyp phenotype and that other sites of
Phex expression and/or additional factors are likely to be
important in the pathogenesis of XLH.
Overexpression of Phex in Osteoblasts Fails to Rescue
the Hyp Mouse Phenotype*
*
This work was supported in part by NIAMS Grants RO1-AR37308
and RO1-AR43468 from the National Institutes of Health (to L. D. Q.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: P. O. Box 3036, DUMC,
Durham, NC 27710. Tel.: 919-660-6853; Fax: 919-684-4476; E-mail:
Quarl001@mc.duke.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Liu, L. Vierthaler, W. Tang, J. Zhou, and L. D. Quarles FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23 J. Am. Soc. Nephrol., December 1, 2008; 19(12): 2342 - 2350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Martin, V. David, J. S. Laurence, P. M. Schwarz, E. M. Lafer, A.-M. Hedge, and P. S. N. Rowe Degradation of MEPE, DMP1, and Release of SIBLING ASARM-Peptides (Minhibins): ASARM-Peptide(s) Are Directly Responsible for Defective Mineralization in HYP Endocrinology, April 1, 2008; 149(4): 1757 - 1772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Stubbs, S. Liu, W. Tang, J. Zhou, Y. Wang, X. Yao, and L. D. Quarles Role of Hyperphosphatemia and 1,25-Dihydroxyvitamin D in Vascular Calcification and Mortality in Fibroblastic Growth Factor 23 Null Mice J. Am. Soc. Nephrol., July 1, 2007; 18(7): 2116 - 2124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu and L. D. Quarles How Fibroblast Growth Factor 23 Works J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1637 - 1647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Liu, J. Zhou, W. Tang, X. Jiang, D. W. Rowe, and L. D. Quarles Pathogenic role of Fgf23 in Hyp mice Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E38 - E49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. White, T. E. Larsson, and M. J. Econs The Roles of Specific Genes Implicated as Circulating Factors Involved in Normal and Disordered Phosphate Homeostasis: Frizzled Related Protein-4, Matrix Extracellular Phosphoglycoprotein, and Fibroblast Growth Factor 23 Endocr. Rev., May 1, 2006; 27(3): 221 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu, W. Tang, J. Zhou, J. R. Stubbs, Q. Luo, M. Pi, and L. D. Quarles Fibroblast Growth Factor 23 Is a Counter-Regulatory Phosphaturic Hormone for Vitamin D J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1305 - 1315. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Liu, T. A. Brown, J. Zhou, Z.-S. Xiao, H. Awad, F. Guilak, and L. D. Quarles Role of Matrix Extracellular Phosphoglycoprotein in the Pathogenesis of X-Linked Hypophosphatemia J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1645 - 1653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Hines, O. I. Kolek, M. D. Jones, S. H. Serey, N. B. Sirjani, P. R. Kiela, P. W. Jurutka, M. R. Haussler, J. F. Collins, and F. K. Ghishan 1,25-Dihydroxyvitamin D3 Down-regulation of PHEX Gene Expression Is Mediated by Apparent Repression of a 110 kDa Transfactor That Binds to a Polyadenine Element in the Promoter J. Biol. Chem., November 5, 2004; 279(45): 46406 - 46414. [Abstract] [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. Kveiborg, G. Sabatakos, R. Chiusaroli, M. Wu, W. M. Philbrick, W. C. Horne, and R. Baron {Delta}FosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms Mol. Cell. Biol., April 1, 2004; 24(7): 2820 - 2830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Brewer, L. Canaff, G. N. Hendy, and H. S. Tenenhouse Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3 Am J Physiol Renal Physiol, April 1, 2004; 286(4): F739 - F748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Bai, D. Miao, D. Panda, S. Grady, M. D. McKee, D. Goltzman, and A. C. Karaplis Partial Rescue of the Hyp Phenotype by Osteoblast-Targeted PHEX (Phosphate-Regulating Gene with Homologies to Endopeptidases on the X Chromosome) Expression Mol. Endocrinol., December 1, 2002; 16(12): 2913 - 2925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Jan De Beur and M. A. Levine Molecular Pathogenesis of Hypophosphatemic Rickets J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2467 - 2473. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |