TIEG and estrogen modulate SOST expression in the murine skeleton.
TIEG and estrogen modulate SOST expression in the murine skeleton.
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DOI：
10.1002/jcp.26211
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发表时间：
2018-04
影响因子：
5.6
通讯作者：
Hawse JR
中科院分区：
文献类型：
--
作者：
Subramaniam M;Pitel KS;Bruinsma ES;Monroe DG;Hawse JR
TIEG敲除（KO）小鼠表现出女性特异性骨质减少表型，并且人类中TIEG的表达改变与骨质疏松症相关。基因表达谱研究将硬化蛋白鉴定为相对于WT同窝出生小鼠的TIEG KO小鼠的长骨中最高度上调的转录物之一，表明TIEG可以调节SOST表达。TIEG被证明基本上抑制SOST启动子活性和TIEG功能的调控元件，通过使用启动子缺失和染色质免疫沉淀测定来鉴定。使用shRNA和CRISPR-Cas9技术敲低IDG-SW 3骨细胞中的TIEG导致SOST表达增加和矿化延迟，模拟了从TIEG KO小鼠骨骼获得的结果。鉴于TIEG是雌激素调节的基因，并且由于激素环境的变化影响SOST表达，我们在WT和TIEG KO小鼠中进行了卵巢切除术（OVX）和雌激素替代疗法（ERT）研究，随后对股骨的皮质和小梁区室进行了miRNA和mRNA测序。与松质骨相比，皮质骨中的SOST表达水平相当高。在皮质骨中，仅WT小鼠OVX后SOST表达增加，两种基因型在ERT后均受到抑制。相反，骨小梁中SOST表达在OVX后降低，在ERT后显著增加。有趣的是，许多预测靶向硬化蛋白的miRNA响应于OVX和ERT表现出相反的表达水平。这些数据暗示了TIEG和雌激素调节的miRNA在调节骨中SOST表达中的重要作用。
TIEG knockout (KO) mice exhibit a female-specific osteopenic phenotype and altered expression of TIEG in humans is associated with osteoporosis. Gene expression profiling studies identified sclerostin as one of the most highly up-regulated transcripts in the long bones of TIEG KO mice relative to WT littermates suggesting that TIEG may regulate SOST expression. TIEG was shown to substantially suppress SOST promoter activity and the regulatory elements through which TIEG functions were identified using promoter deletion and chromatin immunoprecipitation assays. Knockdown of TIEG in IDG-SW3 osteocyte cells using shRNA and CRISPR-Cas9 technology resulted in increased SOST expression and delayed mineralization, mimicking the results obtained from TIEG KO mouse bones. Given that TIEG is an estrogen regulated gene, and since changes in the hormonal milieu affect SOST expression, we performed ovariectomy (OVX) and estrogen replacement therapy (ERT) studies in WT and TIEG KO mice followed by miRNA and mRNA sequencing of cortical and trabecular compartments of femurs. SOST expression levels were considerably higher in cortical bone compared to trabecular bone. In cortical bone, SOST expression was increased following OVX only in WT mice and was suppressed following ERT in both genotypes. In contrast, SOST expression in trabecular bone was decreased following OVX and significantly increased following ERT. Interestingly, a number of miRNAs that are predicted to target sclerostin exhibited inverse expression levels in response to OVX and ERT. These data implicate important roles for TIEG and estrogen-regulated miRNAs in modulating SOST expression in bone.
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影响因子：
6.2
作者：
Jastrzebski, Sandra;Kalinowski, Judith;Stolina, Marina;Mirza, Faryal;Torreggiani, Elena;Kalajzic, Ivo;Won, Hee Yeon;Lee, Sun-Kyeong;Lorenzo, Joseph
通讯作者：
Lorenzo, Joseph
影响因子：
4
作者：
Hawse, J. R.;Subramaniam, M.;Spelsberg, T. C.
通讯作者：
Spelsberg, T. C.
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：
4.1
作者：
Bensamoun, Sabine F.;Hawse, John R.;Spelsberg, Thomas C.
通讯作者：
Spelsberg, Thomas C.
影响因子：
4
作者：
Johnsen, SA;Subramaniam, M;Spelsberg, TC
通讯作者：
Spelsberg, TC