Journal of Biological Chemistry
Volume 277, Issue 5, 1 February 2002, Pages 3686-3697
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METABOLISM AND BIOENERGETICS
Overexpression of Phex in Osteoblasts Fails to Rescue the Hyp Mouse Phenotype*

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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 inHyp-derived osteoblasts (TMOb-Hyp) in vitro. Targeted overexpression of Phex to osteoblasts of OG2 Phex transgenic Hyp mice normalizedPhex endopeptidase activity in bone but failed to correct the hypophosphatemia, rickets, or osteomalacia. OG2 Phextransgenic 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 Phexfunction 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 thePhex substrate FGF-23 in osteoblasts. Taken together, thesein vivo and in vitro data indicate that expression of Phex in osteoblasts is not sufficient to rescue the Hyp phenotype and that other sites ofPhex expression and/or additional factors are likely to be important in the pathogenesis of XLH.

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Published, JBC Papers in Press, November 16, 2001, DOI 10.1074/jbc.M107707200

*

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.