ΔFosB induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms
ΔFosB induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms
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DOI：
10.1128/mcb.24.7.2820-2830.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Baron, R
中科院分区：
文献类型：
--
作者：
Kveiborg, M;Sabatakos, G;Baron, R
成骨细胞和脂肪细胞可以从共同的骨髓间充质前体发育而来。在神经元特异性烯醇化酶（NSE）启动子的控制下，过表达AP-1转录因子DeltaFosB的转基因小鼠表现出骨形成显著增加和脂肪形成减少。为了确定这两种表型是否相关，我们通过使用骨钙素（OG 2）启动子将小鼠中DeltaFosB的过表达靶向成骨细胞。OG 2-DeltaFosB小鼠表现出成骨细胞数量增加和成骨细胞表型，但脂肪细胞分化正常。这一结果坚定地表明，骨骼表型是细胞自主的成骨细胞谱系和独立的脂肪细胞的形成。它还强烈表明，NSE-DeltaFosB小鼠的脂肪表型减少与成骨细胞谱系的变化无关。在体外，DeltaFosB在前脂肪细胞3 T3-L1细胞系中的过表达对脂肪细胞分化几乎没有影响，而它阻止了多潜能基质细胞系ST 2中脂肪形成转录因子的诱导。此外，DeltaFosB同种型结合并改变了C/EBP β的DNA结合能力。因此，DeltaFosB对脂肪细胞分化的抑制作用似乎发生在干细胞定型的早期阶段，影响C/EBP β功能。结论DeltaFosB转基因小鼠成骨细胞和脂肪细胞分化的变化是由独立的细胞自主机制引起的。
Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing DeltaFosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis. To determine whether the two phenotypes were linked, we targeted overexpression of DeltaFosB in mice to the osteoblast by using the osteocalcin (OG2) promoter. OG2-DeltaFosB mice demonstrated increased osteoblast numbers and an osteosclerotic phenotype but normal adipocyte differentiation. This result firmly establishes that the skeletal phenotype is cell autonomous to the osteoblast lineage and independent of adipocyte formation. It also strongly suggests that the decreased fat phenotype of NSE-DeltaFosB mice is independent of the changes in the osteoblast lineage. In vitro, overexpression of DeltaFosB in the preadipocytic 3T3-L1 cell line had little effect on adipocyte differentiation, whereas it prevented the induction of adipogenic transcription factors in the multipotential stromal cell line ST2. Also, DeltaFosB isoforms bound to and altered the DNA-binding capacity of C/EBPbeta. Thus, the inhibitory effect of DeltaFosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C/EBPbeta functions. It is concluded that the changes in osteoblast and adipocyte differentiation in DeltaFosB transgenic mice result from independent cell-autonomous mechanisms.