Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice.
Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice.
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DOI：
10.1002/jbmr.3351
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Monroe DG
中科院分区：
文献类型：
--
作者：
Farr JN;Weivoda MM;Nicks KM;Fraser DG;Negley BA;Onken JL;Thicke BS;Ruan M;Liu H;Forrest D;Hawse JR;Khosla S;Monroe DG
临床上需要寻找治疗骨质疏松症的新的分子靶点，特别是那些在刺激骨形成的同时抑制骨吸收的分子靶点。我们先前在过表达研究中发现，维甲酸受体相关孤儿受体β(Rorβ)在体外抑制成骨细胞的分化。此外，在小鼠和人的骨髓间充质基质细胞中，随着年龄的增长，Rorβ的表达都显著增加。在这里，我们通过体外和体内研究相结合的方法，确立了RoRβ在调节骨代谢中的关键作用。我们使用簇状规则间隔短回文重复序列(CRISPR)/CAS9基因编辑来证明成骨细胞中RORβ的缺失增强了WNT信号，特别是通过增加WNT靶基因TCF7和OPG启动子中的β-连环蛋白与T细胞因子/淋巴增强因子(TCFDNA/LEF)结合位点的募集。这导致成骨基因的表达增加，并通过增加骨保护素的分泌抑制了破骨细胞的形成，这是RORβ缺陷细胞的结果。与我们的体外数据一致，雌性和雄性小鼠中Rorβ的基因缺失都会导致骨量和微结构随着年龄的增长而保存下来，这是因为骨形成增加，伴随着吸收的减少。RORβ−/−小鼠骨骼表型的改善也与TCF7和OPG骨蛋白水平的增加有关。这些数据表明，丢失RoRβ具有有益的骨骼效应，它通过增加骨形成和减少骨吸收，至少部分是通过β依赖的连环蛋白激活Wnt途径。因此，抑制RORβ代表了一种潜在地预防或逆转骨质疏松的新方法。
There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow–derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorβ in osteoblasts enhances Wnt signaling, specifically through increased recruitment of β-catenin to T-cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg. This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorβ-deficient cells. Consistent with our in vitro data, genetic deletion of Rorβ in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorβ−/− mice was also associated with increased bone protein levels of TCF7 and OPG. These data demonstrate that loss of Rorβ has beneficial skeletal effects by increasing bone formation and decreasing bone resorption, at least in part through β-catenin–dependent activation of the Wnt pathway. Thus, inhibition of Rorβ represents a novel approach to potentially prevent or reverse osteoporosis.
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DOI：
10.1621/nrs.07003
发表时间：
2009
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Jetten AM
通讯作者：
Jetten AM
影响因子：
4
作者：
Itoh, Shousaku;Aubin, Jane E.
通讯作者：
Aubin, Jane E.
影响因子：
64.5
作者：
Nakashima, K;Zhou, X;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
11.2
作者：
Cicek，M;Fukuyama，R;Casey，G
通讯作者：
Casey，G
影响因子：
3.7
作者：
Farr JN;Roforth MM;Fujita K;Nicks KM;Cunningham JM;Atkinson EJ;Therneau TM;McCready LK;Peterson JM;Drake MT;Monroe DG;Khosla S
通讯作者：
Khosla S