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J. Biol. Chem., Vol. 277, Issue 5, 3686-3697, February 1, 2002
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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.
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