R-spondin 3 deletion induces Erk phosphorylation to enhance Wnt signaling and promote bone formation in the appendicular skeleton.
R-spondin 3 deletion induces Erk phosphorylation to enhance Wnt signaling and promote bone formation in the appendicular skeleton.
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DOI：
10.7554/elife.84171
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发表时间：
2022-11-02
期刊：
影响因子：
7.7
通讯作者：
Baron R
中科院分区：
文献类型：
--
作者：
Nagano K;Yamana K;Saito H;Kiviranta R;Pedroni AC;Raval D;Niehrs C;Gori F;Baron R
Wnt信号传导的激活导致高骨密度。四种分泌糖蛋白的R-spondin家族（Rspo1 - 4）放大Wnt信号传导。在人类中，RSPO3变体与骨密度密切相关。在这里，我们研究了Rspo3在小鼠骨骼稳态中的作用。使用一套全面的小鼠遗传和机制研究，我们表明，在appropriate骨骼，Rspo3单倍不足和Rspo3靶向删除Runx2+骨祖细胞导致骨小梁骨量增加，成骨细胞和骨形成的数量增加。与此相反，并强调了Wnt信号传导在骨骼稳态调节中的复杂性，我们表明，骨祖细胞中的Rspo3缺失导致中轴骨骼中的相反表型，即，椎体骨小梁量低。从机制上讲，Rspo3缺乏损害了Dkk1对Wnt信号传导激活和骨量的抑制作用。我们证明，Rspo3缺陷导致Erk信号转导的激活，这反过来又稳定了β-连环蛋白和Wnt信号转导的激活。我们的数据表明，Rspo3单倍体不足/缺陷通过激活Erk信号传导增强经典Wnt信号传导，以有利于成骨细胞生成、骨形成和骨量。
Activation of Wnt signaling leads to high bone density. The R-spondin family of four secreted glycoproteins (Rspo1-4) amplifies Wnt signaling. In humans, RSPO3 variants are strongly associated with bone density. Here, we investigated the role of Rspo3 in skeletal homeostasis in mice. Using a comprehensive set of mouse genetic and mechanistic studies, we show that in the appendicular skeleton, Rspo3 haplo-insufficiency and Rspo3 targeted deletion in Runx2+ osteoprogenitors lead to an increase in trabecular bone mass, with increased number of osteoblasts and bone formation. In contrast and highlighting the complexity of Wnt signaling in the regulation of skeletal homeostasis, we show that Rspo3 deletion in osteoprogenitors results in the opposite phenotype in the axial skeleton, i.e., low vertebral trabecular bone mass. Mechanistically, Rspo3 deficiency impairs the inhibitory effect of Dkk1 on Wnt signaling activation and bone mass. We demonstrate that Rspo3 deficiency leads to activation of Erk signaling which in turn, stabilizes β-catenin and Wnt signaling activation. Our data demonstrate that Rspo3 haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling, to favor osteoblastogenesis, bone formation, and bone mass.
影响因子：
3.8
作者：
Ko FC;Van Vliet M;Ellman R;Grasso D;Brooks DJ;Spatz JM;Conlon C;Aguirre JI;Wronski TJ;Bouxsein ML
通讯作者：
Bouxsein ML
DOI：
10.1152/ajpendo.00383.2021
发表时间：
2022-03-01
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
--
作者：
Nilsson KH;Wu J;Gustafsson KL;El Shahawy M;Koskela A;Tuukkanen J;Tuckermann J;Henning P;Lerner UH;Ohlsson C;Movérare-Skrtic S
通讯作者：
Movérare-Skrtic S