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VDR Haploinsufficiency Impacts Body Composition and Skeletal Acquisition in a Gender-Specific Manner

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Abstract

The vitamin D receptor (VDR) is crucial for virtually all of vitamin D’s actions and is thought to be ubiquitously expressed. We hypothesized that disruption of one allele of the VDR gene would impact bone development and would have metabolic consequences. Body composition and bone mass (BMD) in VDR heterozygous (VDR HET) mice were compared to those obtained in male and female VDR KO and WT mice at 8 weeks of age. Male mice were also evaluated at 16 weeks, and bone marrow mesenchymal stem cell (MSC) differentiation was evaluated in VDR female mice. Additionally, female VDR HET and WT mice received intermittent PTH treatment or vehicle (VH) for 4 weeks. BMD was determined at baseline and after treatment. MRI was done in vivo at the end of treatment; μCT and bone histomorphometry were performed after killing the animals. VDR HET male mice had normal skeletal development until 16 weeks of age but showed significantly less gain in fat mass than WT mice. In contrast, female VDR HET mice showed decreased total-body BMD at age 8 weeks but had a normal skeletal response to PTH. MSC differentiation was also impaired in VDR HET female mice. Thus, female VDR HET mice show early impairment in bone acquisition, while male VDR HET mice exhibit a lean phenotype. Our results indicate that the VDR HET mouse is a useful model for studying the metabolic and skeletal impact of decreased vitamin D sensitivity.

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Acknowledgments

We thank Terry M. Handerson and Marilena Preda for technical assistance in μCT and MRI exams, respectively. F. J. A. P. received financial support from the National Council for Scientific and Technological Development (CNPq), Brazil (201650/2008-8). I. D.-P. received financial support from CAPES, Brazil (0102-09-1).

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Authors and Affiliations

  1. Maine Medical Center Research Institute, Research Drive 81, Scarborough, ME, 04074-7205, USA

    Francisco J. A. de Paula, Ingrid Dick-de-Paula, Sheila Bornstein, Bahman Rostama, Phuong Le & Clifford J. Rosen

  2. Department of Internal Medicine, School of Medicine of Ribeirão Preto, USP, Av. Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil

    Francisco J. A. de Paula & Ingrid Dick-de-Paula

  3. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, 02115, USA

    Sutada Lotinun

  4. Harvard Medical School and School of Dental Medicine, and Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA

    Roland Baron

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  1. Francisco J. A. de Paula
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Correspondence to Clifford J. Rosen.

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de Paula, F.J.A., Dick-de-Paula, I., Bornstein, S. et al. VDR Haploinsufficiency Impacts Body Composition and Skeletal Acquisition in a Gender-Specific Manner. Calcif Tissue Int 89, 179–191 (2011). https://doi.org/10.1007/s00223-011-9505-1

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  • DOI: https://doi.org/10.1007/s00223-011-9505-1

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