Misexpression of CCAAT/enhancer binding protein beta causes osteopenia.
Misexpression of CCAAT/enhancer binding protein beta causes osteopenia.
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DOI：
10.1677/joe-08-0514
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发表时间：
2009-05
期刊：
影响因子：
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通讯作者：
Canalis E
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文献类型：
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作者：
Zanotti S;Stadmeyer L;Smerdel-Ramoya A;Durant D;Canalis E
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在脂肪形成中起关键作用，但其在成骨细胞形成中的作用尚不清楚，其在出生后骨骼中的功能也不清楚。为了在体内研究成骨细胞中的C/eBPβ，我们在3.8kb的人骨钙素启动子片段的控制下建立了表达全长C/eBPβ的转基因小鼠。在FVB遗传背景下建立了两个转基因株系，并与野生型斜生对照进行了比较。由于骨小梁数量减少，两个C/eBPβ转基因系均表现出骨量减少，骨体积减少30%。每骨周长的成骨细胞数和破骨细胞数没有变化。转C/EBPβ基因的骨髓基质细胞矿化减少，碱性磷酸酶基因表达水平降低。转C/EBPβ基因的颅骨成骨细胞碱性磷酸酶活性降低。为了确定体内CEBPB缺失的后果，比较了CEBPB缺失小鼠和具有相同基因组成的野生型对照小鼠的表型。CEBPB基因缺失的小鼠由于骨小梁数量减少，体重、体脂和骨密度降低，骨体积减少。每骨周长的成骨细胞数和破骨细胞数没有变化。RNAi下调颅骨成骨细胞c/eBPβ表达对成骨细胞分化/功能无影响。在成骨细胞中，CEBPB失活的表型可能继发于全身间接作用和C/EBPβ的直接作用。综上所述，C/EBPβ在骨髓间充质细胞分化中起作用，其在体内的错误表达导致骨量减少。
CCAAT/Enhancer Binding Proteins (C/EBPs) are expressed by osteoblasts and adipocytes during differentiation. C/EBPβ is critical for adipogenesis; however its role in osteoblastogenesis is unclear, and its function in the postnatal skeleton is not known. To study C/EBPβ in osteoblasts in vivo, we created transgenic mice expressing full length C/EBPβ under the control of a 3.8 kilobase fragment of the human osteocalcin promoter. Two transgenic lines were established in an FVB genetic background, and compared to wild type littermate controls. Both C/EBPβ 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/EBPβ transgenics showed reduced mineralization, and reduced alkaline phosphatase mRNA levels. Calvarial osteoblasts from C/EBPβ transgenics displayed reduced alkaline phosphatase activity. To determine the consequences of the Cebpb deletion in vivo, the phenotype of Cebpb null mice was compared to 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/EBPβ down regulation 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/EBPβ in osteoblasts. In conclusion, C/EBPβ plays a role in mesenchymal cell differentiation and its misexpression in vivo causes osteopenia.