School of Dental Medicine, Harvard University, Boston, United States.
German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
Elife. 2022 Nov 2;11:e84171. doi: 10.7554/eLife.84171.
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, haplo-insufficiency and targeted deletion in 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 deletion in osteoprogenitors results in the opposite phenotype in the axial skeleton, i.e., low vertebral trabecular bone mass. Mechanistically, deficiency impairs the inhibitory effect of Dkk1 on Wnt signaling activation and bone mass. We demonstrate that deficiency leads to activation of Erk signaling which in turn, stabilizes β-catenin and Wnt signaling activation. Our data demonstrate that haplo-insufficiency/deficiency boosts canonical Wnt signaling by activating Erk signaling, to favor osteoblastogenesis, bone formation, and bone mass.
Wnt 信号的激活会导致骨密度增加。RSPO 家族的 4 种分泌糖蛋白（RSPO1-4）可放大 Wnt 信号。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。通过一系列全面的小鼠遗传和机制研究，我们表明在附肢骨骼中， 杂合不足和 靶向缺失在 成骨细胞前体中导致小梁骨量增加，成骨细胞数量增加和骨形成增加。相比之下，突出了 Wnt 信号在骨骼稳态调控中的复杂性，我们表明 成骨细胞前体中的缺失导致轴向骨骼的相反表型，即椎骨小梁骨量低。从机制上讲， 缺乏会损害 Dkk1 对 Wnt 信号激活和骨量的抑制作用。我们证明 缺乏会激活 Erk 信号，从而稳定 β-连环蛋白并激活 Wnt 信号。我们的数据表明， 杂合不足/缺乏通过激活 Erk 信号来增强经典 Wnt 信号，从而有利于成骨细胞生成、骨形成和骨量。
