Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
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DOI：
10.1016/j.bone.2019.115062
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发表时间：
2019
期刊：
影响因子：
4.1
通讯作者：
T. Yorgan;H. Sarı;T. Rolvien;S. Windhorst;A. Failla;U. Kornak;R. Oheim;M. Amling;T. Schinke
中科院分区：
文献类型：
--
作者：
T. Yorgan;H. Sarı;T. Rolvien;S. Windhorst;A. Failla;U. Kornak;R. Oheim;M. Amling;T. Schinke
尽管编码肌动蛋白捆绑蛋白质plastin-3的PLS 3失活突变已被鉴定为导致X连锁骨质疏松症，但PLS 3对骨重建的细胞和分子影响尚不清楚。此外，尽管先前的研究已经基于μCT扫描证明了12周龄的Pls 3缺陷小鼠中的中度骨质减少，但是没有基于未脱钙组织学和骨特异性组织形态计量学对这种模型进行分析的报道。为了填补这一知识空白，我们应用了一种深度表型分析方法，并研究了不同年龄的Pls 3缺陷小鼠。令人惊讶的是，我们没有检测到野生型和Pls 3缺陷的同窝仔之间的骨小梁骨量的显着差异，同样的情况下，所有的组织形态学参数确定在12周龄。然而，值得注意的是，在所有年龄组的P1 s3缺陷小鼠中，胫骨和股骨的皮质厚度均显著降低。我们还研究了Pls 3缺陷的原代成骨细胞的体外行为，这些细胞显示出中度受损的矿化能力。值得注意的是，虽然大多数成骨细胞标记物在野生型和Pls 3缺陷培养物之间没有差异表达，但Sfrp 4的表达在后者中显著降低，这是一个潜在的相关发现，因为Sfrp 4失活在小鼠和人类中特别引起皮质变薄。我们最终解决了这个问题，如果Pls 3-缺陷会损害甲状旁腺激素（PTH）的骨合成代谢的影响。为此，我们每天向野生型和Pls 3缺陷小鼠注射甲状旁腺激素，发现无论基因型如何，都有类似的反应。综上所述，我们的数据表明，小鼠Pls 3缺陷仅通过对早期皮质骨获得产生负面影响来重现X连锁骨质疏松症个体的皮质骨表型。
Although inactivating mutations ofPLS3, encoding the actin-bundling protein plastin-3, have been identified to cause X-linked osteoporosis, the cellular and molecular influence of PLS3 on bone remodeling is poorly defined. Moreover, although a previous study has demonstrated moderate osteopenia in 12 week-oldPls3-deficient mice based on μCT scanning, there is no reported analysis of such a model on the basis of undecalcified histology and bone-specific histomorphometry. To fill this knowledge gap we applied a deep phenotyping approach and studiedPls3-deficient mice at different ages. Surprisingly, we did not detect significant differences between wildtype andPls3-deficient littermates with respect to trabecular bone mass, and the same was the case for all histomorphometric parameters determined at 12 weeks of age. Remarkably however, the cortical thickness in both, tibia and femur, was significantly reduced inPls3-deficient mice in all age groups. We additionally studied theex vivobehavior ofPls3-deficient primary osteoblasts, which displayed moderately impaired mineralization capacity. Of note, while most osteoblastogenesis markers were not differentially expressed between wildtype andPls3-deficient cultures, the expression ofSfrp4was significantly reduced in the latter, a potentially relevant finding, since Sfrp4 inactivation, in mice and humans, specifically causes cortical thinning. We finally addressed the question, ifPls3-deficiency would impair the osteoanabolic influence of parathyroid hormone (PTH). For this purpose we applied daily injection of PTH into wildtype andPls3-deficient mice and found a similar response regardless of the genotype. Taken together, our data reveal thatPls3-deficiency in mice only recapitulates the cortical bone phenotype of individuals with X-linked osteoporosis by negatively affecting the early stage of cortical bone acquisition.