Decreased Bone Formation and Osteopenia in Lamin A/C-Deficient Mice
Decreased Bone Formation and Osteopenia in Lamin A/C-Deficient Mice
复制标题
DOI：
10.1371/journal.pone.0019313
复制
发表时间：
2011-04-25
期刊：
影响因子：
3.7
通讯作者：
Duque, Gustavo
中科院分区：
文献类型：
--
作者：
Li, Wei;Yeo, Li Sze;Duque, Gustavo
骨质疏松相关的骨丢失与骨细胞结构的变化有关，骨细胞生成水平低。解释这些变化的机制尚不清楚。虽然最近在体外的证据表明，在成骨细胞的核膜蛋白质的一个新的作用，这些蛋白质在体内骨细胞分化和骨代谢的作用仍然未知。在这项研究中，我们使用核纤层蛋白A/C null（Lmna（-/-））小鼠，以确定核纤层蛋白A/C在体内骨转换和骨结构中的作用。在三周龄时，Lmna（-/-）小鼠股骨的组织学和显微计算机断层扫描测量结果显示，与其野生型同窝仔相比，Lmna（-/-）小鼠的骨量和微结构显著降低。此外，骨表面标准化后的细胞数量定量显示，与WT同窝小鼠相比，Lmna（-/-）小鼠中的成骨细胞和骨细胞数量显著减少。此外，Lmna（-/-）小鼠具有显著较低的破骨细胞数量，其显示出其形状和大小的异常变化。最后，机制分析表明，核纤层蛋白A/C的缺乏与核被膜的MAN-1蛋白的表达增加相关，MAN-1蛋白受核纤层蛋白A/C的密切调节，其也与Runx 2共定位，从而影响其作为成骨转录因子的能力。总之，这些数据清楚地表明，核纤层蛋白A/C的存在是体内正常骨转换所必需的，并且核纤层蛋白A/C的缺乏诱导低骨转换骨量减少，类似于年龄相关性骨丢失的细胞变化。
Age-related bone loss is associated with changes in bone cellularity with characteristically low levels of osteoblastogenesis. The mechanisms that explain these changes remain unclear. Although recent in vitro evidence has suggested a new role for proteins of the nuclear envelope in osteoblastogenesis, the role of these proteins in bone cells differentiation and bone metabolism in vivo remains unknown. In this study, we used the lamin A/C null (Lmna(-/-)) mice to identify the role of lamin A/C in bone turnover and bone structure in vivo. At three weeks of age, histological and micro computed tomography measurements of femurs in Lmna(-/-) mice revealed a significant decrease in bone mass and microarchitecture in Lmna(-/-) mice as compared with their wild type littermates. Furthermore, quantification of cell numbers after normalization with bone surface revealed a significant reduction in osteoblast and osteocyte numbers in Lmna(-/-) mice compared with their WT littermates. In addition, Lmna(-/-) mice have significantly lower osteoclast number, which show aberrant changes in their shape and size. Finally, mechanistic analysis demonstrated that absence of lamin A/C is associated with increase expression of MAN-1 a protein of the nuclear envelope closely regulated by lamin A/C, which also colocalizes with Runx2 thus affecting its capacity as osteogenic transcription factor. In summary, these data clearly indicate that the presence of lamin A/C is necessary for normal bone turnover in vivo and that absence of lamin A/C induces low bone turnover osteopenia resembling the cellular changes of age-related bone loss.