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

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

N1 - © 2015 American Society for Bone and Mineral Research.

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 - A Kinase Anchor Proteins/deficiency

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Animals

KW - Bone Density

KW - Core Binding Factor Alpha 1 Subunit/genetics

KW - Guanine Nucleotide Exchange Factors/deficiency

KW - Haploinsufficiency

KW - Membrane Proteins/genetics

KW - Mice

KW - Mice, Knockout

KW - Minor Histocompatibility Antigens

KW - Osteoporosis/genetics

KW - rho GTP-Binding Proteins/genetics

U2 - 10.1002/jbmr.2534

DO - 10.1002/jbmr.2534

M3 - Journal article

C2 - 25892096

SN - 0884-0431

VL - 30

SP - 1887

EP - 1895

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 10

ER -