Zanotti Stefano, Stadmeyer Lisa, Smerdel-Ramoya Anna, Durant Deena, Canalis Ernesto
Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, Connecticut 06105-1299, USA.
J Endocrinol. 2009 May;201(2):263-74. doi: 10.1677/JOE-08-0514. Epub 2009 Feb 13.
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.
CCAAT/增强子结合蛋白（C/EBPs）在成骨细胞和脂肪细胞分化过程中表达。C/EBPβ对脂肪生成至关重要；然而，其在成骨细胞生成中的作用尚不清楚，且其在出生后骨骼中的功能也不明确。为了在体内研究成骨细胞中的C/EBPβ，我们构建了在人骨钙素启动子3.8 kb片段控制下表达全长C/EBPβ的转基因小鼠。在Friend白血病病毒B株遗传背景下建立了两个转基因品系，并与野生型同窝对照进行比较。两个C/EBPβ转基因品系均表现出骨质减少，骨体积减少30%，原因是小梁数量减少。每骨周长的成骨细胞和破骨细胞数量未改变。C/EBPβ转基因小鼠的骨髓基质细胞显示矿化减少，碱性磷酸酶mRNA水平降低。C/EBPβ转基因小鼠的颅骨成骨细胞显示碱性磷酸酶活性降低。为了确定体内Cebpb缺失的后果，将Cebpb基因敲除小鼠的表型与相同遗传组成的野生型对照进行比较。Cebpb基因敲除小鼠体重、体脂和骨矿物质密度降低，骨体积减少，原因是小梁数量减少。每骨周长的成骨细胞和破骨细胞数量未改变。通过RNA干扰下调颅骨成骨细胞中的C/EBPβ对成骨细胞分化/功能没有影响。Cebpb失活的表型可能继发于全身间接效应以及C/EBPβ在成骨细胞中的直接效应。总之，C/EBPβ在间充质细胞分化中起作用，其在体内的错误表达导致骨质减少。
