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The PHEX Transgene Corrects Mineralization Defects in 9-Month-Old Hypophosphatemic Mice

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Abstract

Hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. While osteoblast-specific expression of the PHEX transgene has been reported to decrease the phosphate wasting associated with the disease in male hypophosphatemic (HYP) mice, there are reports that the mineralization defect is only partially corrected in young animals. To test the hypothesis that osteoblast-specific expression of the PHEX gene for a longer time would correct the mineralization defect, this study examined the bones of 9-month-old male and female HYP mice and their wild-type controls with or without expression of the transgene under a collagen type I promoter. Serum phosphate levels, alkaline phosphatase activity, and FGF23 levels were also measured. Mineral analyses based on wide-angle X-ray diffraction, Fourier transform-infrared (FT-IR) spectroscopy, and FT-IR imaging confirmed the decreased mineral content and increased mineral crystal size in male HYP humerii compared to wild-type males and females with or without the transgene and in female HYP mice with or without the transgene. There was a significant increase in mineral content and a decrease in crystallinity in the HYP males’ bones with the transgene, compared to those without. Of interest, expression of the transgene in wild-type animals significantly increased the mineral content in both males and females without having a detectable effect on crystallinity or carbonate content. In contrast to the bones, based on micro-computed tomography and FT-IR imaging, at 9 months there were no significant differences between the HYP and the WT teeth, precluding analysis of the effect of the transgene.

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Acknowledgments

This work was supported by NIH Grant DE04141 (A.L.B.), Hospital for Special Surgery Musculoskeletal Repair and Regeneration Core Center Grant NIH P30-AR046121 (A.L.B.), and the Traveler’s Summer Fellowship Program (A.F.), NIH Center for Research Translation Award P50-AR054086 (T.O.C.), and the Yale Core Center for Musculoskeletal Disorders (NIH P30-AR46032).

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Authors and Affiliations

  1. Musculoskeletal Integrity Program, Hospital for Special Surgery, affiliated with Weill Medical College of Cornell University, 535 East 70th Street, New York, NY, 10021, USA

    Adele Boskey, Aaron Frank, Yukiji Fujimoto, Lyudmila Spevak & Kostas Verdelis

  2. Department of Pediatrics, Yale University, New Haven, CT, USA

    Bruce Ellis & Thomas Carpenter

  3. Department of Orthopaedics and Rehabilitation, Yale University, New Haven, CT, USA

    Nancy Troiano

  4. Department of Internal Medicine, Yale University, New Haven, CT, USA

    William Philbrick

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  1. Adele Boskey
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  2. Aaron Frank
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  3. Yukiji Fujimoto
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  4. Lyudmila Spevak
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  5. Kostas Verdelis
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  6. Bruce Ellis
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  7. Nancy Troiano
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  8. William Philbrick
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  9. Thomas Carpenter
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Correspondence to Adele Boskey.

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Boskey, A., Frank, A., Fujimoto, Y. et al. The PHEX Transgene Corrects Mineralization Defects in 9-Month-Old Hypophosphatemic Mice. Calcif Tissue Int 84, 126–137 (2009). https://doi.org/10.1007/s00223-008-9201-y

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  • DOI: https://doi.org/10.1007/s00223-008-9201-y

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