Ageing Bone Research Program, Nepean Clinical School, University of Sydney, Penrith, New South Wales, Australia.
PLoS One. 2011 Apr 25;6(4):e19313. doi: 10.1371/journal.pone.0019313.
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.
年龄相关性骨丢失与成骨细胞活性降低有关，成骨细胞活性降低是其特征之一。这些变化的发生机制尚不清楚。尽管最近的体外证据表明核膜蛋白在成骨细胞发生中具有新的作用，但这些蛋白质在体内骨细胞分化和骨代谢中的作用仍不清楚。在这项研究中，我们使用 lamin A/C 敲除（Lmna⁻/⁻）小鼠来确定 lamin A/C 在体内骨转换和骨结构中的作用。在 3 周龄时，Lmna⁻/⁻小鼠股骨的组织学和微计算机断层扫描测量结果显示，与野生型同窝仔相比，Lmna⁻/⁻小鼠的骨量和微结构明显减少。此外，通过与骨表面归一化来量化细胞数量后，发现 Lmna⁻/⁻小鼠的成骨细胞和破骨细胞数量明显少于 WT 同窝仔。此外，Lmna⁻/⁻小鼠的破骨细胞数量显著减少，其形态和大小也发生了异常变化。最后，机制分析表明， lamin A/C 的缺失与核膜蛋白 MAN-1 的表达增加有关，而 MAN-1 是 lamin A/C 密切调控的蛋白，它也与 Runx2 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， lamin A/C 的存在是体内正常骨转换所必需的，而 lamin A/C 的缺失会导致低骨转换性骨质疏松症，类似于年龄相关性骨丢失的细胞变化。
