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,*

Article first published online: 10 MAY 2015

DOI: 10.1002/jbmr.2534


Additional Information

How to Cite

Koide, H., Holmbeck, K., Lui, J. C., Guo, X. C., Driggers, P., Chu, T., Tatsuno, I., Quaglieri, C., Kino, T., Baron, J., Young, M. F., Robey, P. G. and Segars, J. H. (2015), Mice Deficient in AKAP13 (BRX) Are Osteoporotic and Have Impaired Osteogenesis. J Bone Miner Res. doi: 10.1002/jbmr.2534

Author Information

  1. 1

    Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA

  2. 2

    Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA

  3. 3

    Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA

  4. 4

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

* Address correspondence to: James H. Segars, MD, Division of Reproductive Sciences and Women's Health Research, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, 720 Rutland Avenue, Room 624 Ross, Baltimore, MD 21205, USA. E-mail: jsegars2@jhmi.edu

  1. Current address: James H. Segars, MD, Division of Reproductive Sciences and Women's Health Research, Department of Gynecology and Obstetrics, 720 Rutland Avenue, Room 624 Ross Building, Baltimore, MD 21205, USA. E-mail: j segars2@jhmi.edu

Publication History

  1. Article first published online: 10 MAY 2015
  2. Accepted manuscript online: 18 APR 2015 05:26PM EST
  3. Manuscript Accepted: 15 APR 2015
  4. Manuscript Revised: 3 APR 2015
  5. 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, aka 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 a corresponding reduction in osteoblast number, but no impairment of mature osteoblast activity. © 2015 American Society for Bone and Mineral Research.

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