Misexpression of CCAAT/enhancer binding protein beta causes osteopenia.
CCAAT/enhancer binding proteins (C/EBPs) are expressed by osteoblasts and adipocytes during differentiation. C/EBP beta is critical for adipogenesis; however, its role in osteoblastogenesis is unclear, and its function in the postnatal skeleton is not known. To study C/EBP beta in osteoblasts in vivo, we created transgenic mice expressing full length C/EBP beta under the control of a 3.8 kb fragment of the human osteocalcin promoter. Two transgenic lines were established in a friend leukemia virus strain B genetic background, and compared with wild type littermate controls. Both C/EBP beta transgenic lines exhibited osteopenia, with a 30% decrease in bone volume, due to a decrease in trabecular number. The number of osteoblasts and osteoclasts per bone perimeter was not changed. Bone marrow stromal cells from C/EBP beta transgenics showed reduced mineralization, and reduced alkaline phosphatase mRNA levels. Calvarial osteoblasts from C/EBP beta transgenics displayed reduced alkaline phosphatase activity. To determine the consequences of the Cebpb deletion in vivo, the phenotype of Cebpb null mice was compared with that of wild type controls of identical genetic composition. Cebpb null mice exhibited reduced weight, body fat, and bone mineral density, and decreased bone volume, due to a decrease in trabecular number. The number of osteoblasts and osteoclasts per bone perimeter was not changed. C/EBP beta downregulation by RNA interference in calvarial osteoblasts had no effect on osteoblast differentiation/function. The phenotype of the Cebpb inactivation may be secondary to systemic indirect effects, and to direct effects of C/EBP beta in osteoblasts. In conclusion, C/EBP beta plays a role in mesenchymal cell differentiation and its misexpression in vivo causes osteopenia.
Zanotti
Stefano
S
Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, Connecticut 06105-1299, USA.
Stadmeyer
Lisa
L
Smerdel-Ramoya
Anna
A
Durant
Deena
D
Canalis
Ernesto
E
D000818:Animals; D015519:Bone Density / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005269:Femur / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology
D022782:CCAAT-Enhancer-Binding Protein-beta