Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis

Hisashi Koide, Kenn Holmbeck, Julian C. Lui, Xiaoxiao C. Guo, Paul Driggers, Tiffany Chu, Ichiro Tatsuno, Caroline Quaglieri, Tomoshige Kino, Jeffrey Baron, Marian F. Young, Pamela G. Robey, James H. Segars

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1887-1895
Number of pages9
JournalJournal of Bone and Mineral Research
Volume30
Issue number10
DOIs
Publication statusPublished - 1 Oct 2015
Externally publishedYes

Fingerprint

Osteogenesis
Osteoblasts
Cyclic AMP-Dependent Protein Kinases
Bone and Bones
Alkaline Phosphatase
Stem Cells
Guanine Nucleotide Exchange Factors
rho-Associated Kinases
Bone Remodeling
Bone Development
Glucocorticoid Receptors
Bone Marrow Cells
Estrogen Receptors
Bone Density
Femur
Glucocorticoids
Extracellular Matrix
Estrogens
Transcription Factors
Fibroblasts

Keywords

  • BRX
  • osteogenesis
  • osteoporosis
  • RHO-GEF
  • Runx2

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Koide, H., Holmbeck, K., Lui, J. C., Guo, X. C., Driggers, P., Chu, T., ... Segars, J. H. (2015). Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis. Journal of Bone and Mineral Research, 30(10), 1887-1895. https://doi.org/10.1002/jbmr.2534

Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis. / Koide, Hisashi; Holmbeck, Kenn; Lui, Julian C.; Guo, Xiaoxiao C.; Driggers, Paul; Chu, Tiffany; Tatsuno, Ichiro; Quaglieri, Caroline; Kino, Tomoshige; Baron, Jeffrey; Young, Marian F.; Robey, Pamela G.; Segars, James H.

In: Journal of Bone and Mineral Research, Vol. 30, No. 10, 01.10.2015, p. 1887-1895.

Research output: Contribution to journalArticle

Koide, H, Holmbeck, K, Lui, JC, Guo, XC, Driggers, P, Chu, T, Tatsuno, I, Quaglieri, C, Kino, T, Baron, J, Young, MF, Robey, PG & Segars, JH 2015, 'Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis', Journal of Bone and Mineral Research, vol. 30, no. 10, pp. 1887-1895. https://doi.org/10.1002/jbmr.2534
Koide, Hisashi ; Holmbeck, Kenn ; Lui, Julian C. ; Guo, Xiaoxiao C. ; Driggers, Paul ; Chu, Tiffany ; Tatsuno, Ichiro ; Quaglieri, Caroline ; Kino, Tomoshige ; Baron, Jeffrey ; Young, Marian F. ; Robey, Pamela G. ; Segars, James H. / Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis. In: Journal of Bone and Mineral Research. 2015 ; Vol. 30, No. 10. pp. 1887-1895.
@article{f016ef8e14d54f83990c98e6369214ba,
title = "Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis",
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.",
keywords = "BRX, osteogenesis, osteoporosis, RHO-GEF, Runx2",
author = "Hisashi Koide and Kenn Holmbeck and Lui, {Julian C.} and Guo, {Xiaoxiao C.} and Paul Driggers and Tiffany Chu and Ichiro Tatsuno and Caroline Quaglieri and Tomoshige Kino and Jeffrey Baron and Young, {Marian F.} and Robey, {Pamela G.} and Segars, {James H.}",
year = "2015",
month = "10",
day = "1",
doi = "10.1002/jbmr.2534",
language = "English",
volume = "30",
pages = "1887--1895",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - Mice deficient in AKAP13 (BRX) are osteoporotic and have impaired osteogenesis

AU - Koide, Hisashi

AU - Holmbeck, Kenn

AU - Lui, Julian C.

AU - Guo, Xiaoxiao C.

AU - Driggers, Paul

AU - Chu, Tiffany

AU - Tatsuno, Ichiro

AU - Quaglieri, Caroline

AU - Kino, Tomoshige

AU - Baron, Jeffrey

AU - Young, Marian F.

AU - Robey, Pamela G.

AU - Segars, James H.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - BRX

KW - osteogenesis

KW - osteoporosis

KW - RHO-GEF

KW - Runx2

UR - http://www.scopus.com/inward/record.url?scp=84942193026&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942193026&partnerID=8YFLogxK

U2 - 10.1002/jbmr.2534

DO - 10.1002/jbmr.2534

M3 - Article

VL - 30

SP - 1887

EP - 1895

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 10

ER -