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.
authors.affiliation: 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.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Koide
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Kenn
authors.initials: K
authors.lastname: Holmbeck
authors.affiliation: 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.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Lui
authors.affiliation: 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.
authors.forename: Xiaoxiao C
authors.initials: XC
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Driggers
authors.affiliation: 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.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chu
authors.affiliation: Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Chiba, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tatsuno
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Quaglieri
authors.affiliation: 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.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.affiliation: 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.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baron
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Marian F
authors.initials: MF
authors.lastname: Young
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
authors.affiliation: 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.
authors.forename: James H
authors.initials: JH
authors.lastname: Segars
mesh_terms: D054758:A Kinase Anchor Proteins / Q000172:deficiency*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015519:Bone Density; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency*; D057895:Haploinsufficiency; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C526201:Akap13 protein, mouse; C480020:Atrnl1 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; C493716:Runx2 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: BRX; OSTEOGENESIS; OSTEOPOROSIS; RHO-GEF; RUNX2