Deficiency of Sef Is Associated With Increased Postnatal Cortical Bone Mass by Regulating Runx2 Activity
Deficiency of Sef Is Associated With Increased Postnatal Cortical Bone Mass by Regulating Runx2 Activity
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DOI：
10.1002/jbmr.2114
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发表时间：
2014-05-01
影响因子：
6.2
通讯作者：
Friesel, Robert E.
中科院分区：
文献类型：
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作者：
He, Qing;Yang, Xuehui;Friesel, Robert E.
Sef（与FGF基因表达相似）是成纤维细胞生长因子（FGF）信号传导的反馈抑制剂，部分通过与FGF受体结合并抑制其活化来发挥作用。在小鼠和人类中的遗传研究表明成纤维细胞生长因子信号传导在骨生长和稳态中的重要作用。因此，我们研究了Sef是否在骨骼获得和重塑中起作用。在体外成骨细胞分化过程中，Sef表达增加，并且Sef+/-小鼠的LacZ染色显示Sef在新生小鼠和成年小鼠的骨膜和软骨-骨结合部中高表达。通过显微计算机断层扫描（micro-CT），Sef整体缺失的小鼠显示皮质骨厚度、骨体积和骨膜周长增加。皮质骨的组织形态计量学分析显示成骨细胞数量显著增加。有趣的是，与野生型小鼠相比，通过显微CT和组织形态计量学，Sef-/-小鼠在骨小梁中显示出非常小的差异。与野生型骨髓细胞相比，在成骨培养基中生长的Sef-/-小鼠的骨髓细胞表现出增殖增加和成骨细胞分化增加。来自Sef-/-小鼠的骨髓细胞显示出增强的FGF 2诱导的ERK通路活化，而来自Sef转基因小鼠的骨髓细胞显示出减少的FGF 2诱导的信号传导。FGF 2诱导的乙酰化和Runx 2的稳定性在Sef-/-骨髓细胞中增强，而过表达的Sef抑制Runx 2响应荧光素酶报告活性。在体外试验中，相对于野生型对照，Sef-/-小鼠的骨髓表现出增强的造血谱系依赖性和成骨细胞依赖性破骨细胞生成和增加的骨吸收活性，而过度表达Sef抑制破骨细胞分化。总之，这些研究表明，Sef在成骨细胞和破骨细胞谱系中具有特定作用，并且其缺乏导致成骨细胞和破骨细胞活性增加，皮质骨量净增加。(c)2014年美国骨与矿物质研究学会。
Sef (similar expression to fgf genes) is a feedback inhibitor of fibroblast growth factor (FGF) signaling and functions in part by binding to FGF receptors and inhibiting their activation. Genetic studies in mice and humans indicate an important role for fibroblast growth factor signaling in bone growth and homeostasis. We, therefore, investigated whether Sef had a function role in skeletal acquisition and remodeling. Sef expression is increased during osteoblast differentiation in vitro, and LacZ staining of Sef+/- mice showed high expression of Sef in the periosteum and chondro-osseous junction of neonatal and adult mice. Mice with a global deletion of Sef showed increased cortical bone thickness, bone volume, and increased periosteal perimeter by micro-computed tomography (micro-CT). Histomorphometric analysis of cortical bone revealed a significant increase in osteoblast number. Interestingly, Sef-/- mice showed very little difference in trabecular bone by micro-CT and histomorphometry compared with wild-type mice. Bone marrow cells from Sef-/- mice grown in osteogenic medium showed increased proliferation and increased osteoblast differentiation compared with wild-type bone marrow cells. Bone marrow cells from Sef-/- mice showed enhanced FGF2-induced activation of the ERK pathway, whereas bone marrow cells from Sef transgenic mice showed decreased FGF2-induced signaling. FGF2-induced acetylation and stability of Runx2 was enhanced in Sef-/- bone marrow cells, whereas overexpression of Sef inhibited Runx2-responsive luciferase reporter activity. Bone marrow from Sef-/- mice showed enhanced hematopoietic lineage-dependent and osteoblast-dependent osteoclastogenesis and increased bone resorptive activity relative to wild-type controls in in vitro assays, whereas overexpression of Sef inhibited osteoclast differentiation. Taken together, these studies indicate that Sef has specific roles in osteoblast and osteoclast lineages and that its absence results in increased osteoblast and osteoclast activity with a net increase in cortical bone mass. (c) 2014 American Society for Bone and Mineral Research.