Absence of sclerostin adversely affects B-cell survival.
Absence of sclerostin adversely affects B-cell survival.
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DOI：
10.1002/jbmr.1608
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发表时间：
2012-07
影响因子：
6.2
通讯作者：
Manilay, Jennifer O.
中科院分区：
文献类型：
--
作者：
Cain, Corey J.;Rueda, Randell;McLelland, Bryce;Collette, Nicole M.;Loots, Gabriela G.;Manilay, Jennifer O.
硬化蛋白敲除（Sost−/−）小鼠中成骨细胞活性增加导致全身性骨质增生和由于过度活跃的矿化成骨细胞群而具有小骨髓腔的骨骼。造血细胞的命运决定取决于它们的局部微环境，其包含支持造血干细胞静止和促进B细胞发育的成骨细胞和基质细胞群体。在这项研究中，我们调查了高骨量环境是否影响B细胞的发展，通过利用Sost−/−小鼠，一种模型的骨质疏松症。我们发现，由于所有B细胞发育阶段的细胞凋亡增加，Sost−/−小鼠的骨髓中B细胞特异性耗竭。相反，脾脏中的B细胞功能正常。Sost表达分析证实，Sost主要在骨细胞中表达，而在任何造血谱系中均不表达，这表明Sost−/−小鼠中的B细胞缺陷是非细胞自主的，这一点通过将野生型（WT）骨髓移植到致死性辐照的Sost−/−受体中得到证实。WT→Sost−/−嵌合体显示B细胞减少，而相反的Sost−/−→WT嵌合体则没有，这支持了Sost−/−骨环境不能完全支持正常B细胞发育的观点。前B细胞生长刺激因子Cxcl 12在Sost−/−小鼠的骨髓基质细胞中的表达显著降低，而Wnt靶基因Lef-1和Ccnd 1在B细胞中保持不变。综上所述，这些结果证明了Sost在支持B细胞的骨髓环境调节中的新作用。
Increased osteoblast activity in sclerostin-knockout (Sost−/−) mice results in generalized hyperostosis and bones with small bone marrow cavities due to hyperactive mineralizing osteoblast populations. Hematopoietic cell fate decisions are dependent on their local microenvironment, which contains osteoblast and stromal cell populations that support both hematopoietic stem cell quiescence and facilitate B cell development. In this study, we investigated whether high bone mass environments affect B cell development via the utilization of Sost−/− mice, a model of sclerosteosis. We found the bone marrow of Sost−/− mice to be specifically depleted of B cells, due to elevated apoptosis at all B cell developmental stages. In contrast, B cell function in the spleen was normal. Sost expression analysis confirmed that Sost is primarily expressed in osteocytes and is not expressed in any hematopoietic lineage, which indicated that the B cell defects in Sost−/− mice are non-cell autonomous and this was confirmed by transplantation of wildtype (WT) bone marrow into lethally irradiated Sost−/− recipients. WT→Sost−/− chimeras displayed a reduction in B cells, whereas reciprocal Sost−/−→WT chimeras did not, supporting the idea that the Sost−/− bone environment cannot fully support normal B cell development. Expression of the pre-B cell growth stimulating factor, Cxcl12, was significantly lower in bone marrow stromal cells of Sost−/− mice while the Wnt target genes Lef-1 and Ccnd1 remained unchanged in B cells. Taken together, these results demonstrate a novel role for Sost in the regulation of bone marrow environments that support B cells.
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DOI：
10.4049/jimmunol.181.6.3955
发表时间：
2008-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Malhotra S;Baba Y;Garrett KP;Staal FJ;Gerstein R;Kincade PW
通讯作者：
Kincade PW
影响因子：
4.1
作者：
Horowitz, Mark C.;Fretz, Jackie A.;Lorenzo, Joseph A.
通讯作者：
Lorenzo, Joseph A.
影响因子：
6.2
作者：
Li, Xiaodong;Ominsky, Michael S.;Paszty, Chris
通讯作者：
Paszty, Chris
影响因子：
2.6
作者：
Malhotra, Sachin;Kincade, Paul W.
通讯作者：
Kincade, Paul W.
影响因子：
3.7
作者：
Choi HY;Dieckmann M;Herz J;Niemeier A
通讯作者：
Niemeier A