Original Article

Mice Deficient in AKAP13 (BRX) Are Osteoporotic and Have Impaired Osteogenesis†

  1. Hisashi Koide1,
  2. Kenn Holmbeck2,
  3. Julian C. Lui3,
  4. Xiaoxiao C. Guo1,
  5. Paul Driggers1,
  6. Tiffany Chu1,
  7. Ichiro Tatsuno4,
  8. Caroline Quaglieri1,
  9. Tomoshige Kino1,
  10. Jeffrey Baron3,
  11. Marian F. Young2,
  12. Pamela G. Robey2 and
  13. James H. Segars1,‡,*

DOI: 10.1002/jbmr.2534


Additional Information

Author Information

  1. 1

    Unit of Reproductive Endocrinology, PRAE, NICHD, NIH, Bethesda, MD

  2. 2

    Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, Bethesda, MD

  3. 3

    Program in Developmental Endocrinology and Genetics, NICHD, NIH, Bethesda, MD

  4. 4

    Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Sakura-City, Chiba, Japan

  1. ‡

    Division of Reproductive Sciences and Women's Health Research, Department of Gynecology and Obstetrics, Baltimore, MD

* Corresponding Author: James H. Segars
Division of Reproductive Sciences and Women's Health Research, Department of Gynecology and Obstetrics, 720 Rutland Avenue, Room 624 Ross Buildingm, Baltimore, MD 21205
Phone: 410-614-2000
e-mail: jsegars2@jhmi.edu

  1. †

    This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: [10.1002/jbmr.2534]

Publication History

  1. Accepted manuscript online: 18 APR 2015 05:26PM EST
  2. Manuscript Accepted: 15 APR 2015
  3. Manuscript Revised: 3 APR 2015
  4. Manuscript Received: 12 SEP 2013

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Keywords:

  • Osteoporosis;
  • Brx;
  • Rho-GEF;
  • osteogenesis;
  • Runx2

ABSTRACT

Mechanical stimulation is crucial to bone growth and triggers osteogenic differentiation through a process involving Rho and protein kinase A. We previously cloned a gene (AKAP13, a.k.a. BRX) encoding a Protein kinase A-Anchoring Protein in the N-terminus, a guanine nucleotide-exchange factor for RhoA in the mid-section, coupled to a carboxyl region that binds to estrogen and glucocorticoid nuclear receptors. Because of the critical role of Rho, estrogen and glucocorticoids in bone remodeling, we examined the multifunctional role of Akap13. Akap13 was expressed in bone, and mice haploinsufficient for Akap13 (Akap13+/−) displayed reduced bone mineral density, reduced bone volume/total volume and trabecular number, and increased trabecular spacing; resembling the changes observed in osteoporotic bone. Consistent with the osteoporotic phenotype, Colony Forming Unit-Fibroblast numbers were diminished in Akap13+/− mice, as were osteoblast numbers and extracellular matrix production when compared to control littermates. Transcripts of Runx2, an essential transcription factor for the osteogenic lineage, and alkaline phosphatase (Alp), an indicator of osteogenic commitment, were both reduced in femora of Akap13+/− mice. Knockdown of Akap13 reduced levels of Runx2 and Alp transcripts in immortalized bone marrow stem cells. These findings suggest that Akap13 haploinsufficient mice have a deficiency in early osteogenesis with corresponding reduction in osteoblast number, but no impairment of mature osteoblast activity. This article is protected by copyright. All rights reserved

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