Department of Microbiology, New York University School of Medicine, 550 1st Ave, New York, NY 10016, USA.
Bone. 2011 Oct;49(4):653-61. doi: 10.1016/j.bone.2011.06.008. Epub 2011 Jun 15.
We have previously shown that in osteoblasts Sox2 expression can be induced by Fgfs, and can inhibit Wnt signaling and differentiation. Furthermore, in mice in which Sox2 is conditionally deleted in the osteoblastic lineage, bones are osteopenic, and Sox2 inactivation in cultured osteoblasts leads to a loss of proliferative ability with a senescent phenotype. To help understand the role of Sox2 in osteoblast development we have specifically expressed Sox2 in bone from a Col1α1 promoter, which extended Sox2 expression into more mature osteoblasts. In long bones, trabecular cartilage remodeling was delayed and the transition from endochondral to cortical bone was disrupted, resulting in porous and undermineralized cortical bone. Collagen deposition was disorganized, and patterns of osteoclast activity were altered. Calvarial bones were thinner and parietal bones failed to develop the diploic space. Microarray analysis showed significant up- or downregulation of a variety of genes coding for non-collagenous extracellular matrix proteins, with a number of genes typical of mature osteoblasts being downregulated. Our results position Sox2 as a negative regulator of osteoblast maturation in vivo.
我们之前已经表明，在成骨细胞中 Sox2 的表达可以被 Fgfs 诱导，并能抑制 Wnt 信号通路和分化。此外，在成骨细胞系中条件性缺失 Sox2 的小鼠中，骨骼呈现骨质疏松表型，而 Sox2 在培养的成骨细胞中的失活会导致增殖能力丧失和衰老表型。为了帮助理解 Sox2 在成骨细胞发育中的作用，我们已经特异性地在 Col1α1 启动子驱动下在骨中表达 Sox2，这将 Sox2 的表达延伸到更成熟的成骨细胞中。在长骨中，小梁软骨重塑被延迟，从软骨内成骨到皮质骨的转变被打乱，导致多孔和矿化不足的皮质骨。胶原沉积紊乱，破骨细胞活性模式发生改变。颅骨变薄，顶骨未能形成板障。微阵列分析显示，编码非胶原蛋白细胞外基质蛋白的多种基因的表达水平显著上调或下调，许多与成熟成骨细胞相关的基因下调。我们的结果表明 Sox2 是体内成骨细胞成熟的负调控因子。
