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Impaired Cortical Bone Acquisition and Osteoblast Differentiation in Mice with Osteoblast-Targeted Disruption of Glucocorticoid Signaling

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Abstract

To determine the role of endogenous glucocorticoids in bone, we previously developed transgenic mice in which a 2.3 kb fragment of the Col1a1 promoter drives 11ß-hydroxysteroid dehydrogenase 2 expression in mature osteoblasts. This transgene should inactivate glucocorticoids upstream of all receptor signaling pathways. In the present study, we show that femoral cortical bone area and thickness were approximately 10–15% lower in transgenic mice than in wild-type littermates. Femur length was unchanged, indicating that bone elongation was not affected in this model. Expression of osteocalcin mRNA, pOBCol2.3-GFP (a green fluorescent protein marker of mature osteoblasts), and the formation of mineralized nodules were impaired in ex vivo transgenic primary calvarial cultures. The extent of crystal violet staining in bone marrow cultures, indicative of the number of adherent stromal cells, was also decreased. These data suggest that endogenous glucocorticoids are required for cortical bone acquisition and full osteoblast differentiation. It appears that blocking glucocorticoid signaling in vivo leads to a decrease in the commitment and/or expansion of progenitors entering the osteoblast lineage.

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Acknowledgments

This work was supported by grants R01 AR048602 and P01 AR038933 (to B. E. K.) from the National Institutes of Arthritis and Musculoskeletal Diseases (NIAMS) of the National Institutes of Health. We acknowledge support from the Core Center for Musculoskeletal Disorders (grant P30 AR46026) from NIAMS and the University of Connecticut Health Center Microcomputed Tomography Facility. L. B. S. received support from Skeletal, Craniofacial, and Oral Biology training grant T32 DE007302 from the National Institute of Dental and Craniofacial Research.

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Authors and Affiliations

  1. Department of Medicine, University of Connecticut Health Center, Farmington, CT, 06030, USA

    L. B. Sher & B. E. Kream

  2. Department of Orthodontics, Oral and Maxillofacial Surgery, Pediatric Dentistry, and Advanced Education in Clinical Dentistry, University of Connecticut Health Center, Farmington, CT, 06030, USA

    J. R. Harrison

  3. Department of Orthopedic Surgery, University of Connecticut Health Center, Farmington, CT, 06030, USA

    D. J. Adams

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  1. L. B. Sher
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  2. J. R. Harrison
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  4. B. E. Kream
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Correspondence to B. E. Kream.

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Sher, L.B., Harrison, J.R., Adams, D.J. et al. Impaired Cortical Bone Acquisition and Osteoblast Differentiation in Mice with Osteoblast-Targeted Disruption of Glucocorticoid Signaling. Calcif Tissue Int 79, 118–125 (2006). https://doi.org/10.1007/s00223-005-0297-z

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  • DOI: https://doi.org/10.1007/s00223-005-0297-z

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