Morc3 mutant mice exhibit reduced cortical area and thickness, accompanied by altered haematopoietic stem cells niche and bone cell differentiation.
Morc3 mutant mice exhibit reduced cortical area and thickness, accompanied by altered haematopoietic stem cells niche and bone cell differentiation.
复制标题
DOI：
10.1038/srep25964
复制
发表时间：
2016-05-18
影响因子：
4.6
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Jadhav G;Teguh D;Kenny J;Tickner J;Xu J
Morc 3是一个高度保守的核基质蛋白超家族成员，在染色质重塑、DNA修复、表观遗传调控和细胞衰老中起着重要作用。然而，其在骨稳态中的作用尚不清楚。在本研究中，表型驱动的ENU小鼠诱变筛选显示，Morc 3 mut +/−小鼠表现出皮质面积和厚度减少，皮质孔隙率增加。Morc 3 mut +/−小鼠显示破骨细胞数量和每个骨表面的表面以及骨细胞数量减少，伴随着离体长骨中Rankl/Opg和Sost等基因表达的改变。体外实验显示Sca-1+/c-kit+造血干细胞（HSC）数量显著增加，骨髓巨噬细胞（BMSCs）中衰老相关β-半乳糖苷酶活性显著降低。此外，我们观察到破骨细胞生成和骨吸收的减少伴随着破骨细胞谱系细胞中STAT 1表达的上调。引人注目的是，在Morc 3 mut +/−破骨细胞中，核膜内的Morc 3蛋白定位转移到细胞质。此外，Morc 3 mut +/−小鼠显示成骨细胞分化增加和基因表达改变。总的来说，我们的数据表明，Morc 3是一个以前未报道的调节皮质骨稳态和造血干细胞龛，伴随着改变骨细胞分化。
Morc3, a member of a highly conserved nuclear matrix protein super-family plays an important part in chromatin remodeling, DNA repair, epigenetic regulation and cellular senescence. However, its role in bone homeostasis is not known. In the present study, a phenotype-driven ENU mouse mutagenesis screen revealed that Morc3mut +/− mice exhibit reduced cortical area and thickness with increased cortical porosity. Morc3mut +/− mice displayed reduced osteoclast numbers and surface per bone surface as well as osteocyte numbers, concomitant with altered gene expressions such as Rankl/Opg and Sost in ex vivo long bones. In vitro experiments revealed a significant increase in the number of Sca-1+/c-kit+ haematopoietic stem cells (HSCs), and a significant reduction in senescence associated β-galactosidase activity in bone marrow macrophages (BMMs). In addition, we observed a decrease in osteoclastogenesis and bone resorption accompanied by upregulation of STAT1 expression in osteoclast lineage cells. Strikingly, Morc3 protein localization within the nuclear membrane was shifted to the cytoplasm in Morc3mut +/− osteoclasts. Further, Morc3mut +/− mice displayed increased osteoblast differentiation and altered gene expression. Collectively, our data show that Morc3 is a previously unreported regulator of cortical bone homeostasis and haematopoietic stem cells niche, accompanied by altered bone cell differentiation.