ATP6AP2 是 LRP6/β-catenin 蛋白运输的调节因子,它以细胞类型依赖的方式促进 Wnt/β-catenin 信号传导和骨形成

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-05-29 DOI:10.1038/s41413-024-00335-7
Lei Xiong, Hao-Han Guo, Jin-Xiu Pan, Xiao Ren, Daehoon Lee, Li Chen, Lin Mei, Wen-Cheng Xiong
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引用次数: 0

摘要

Wnt/β-catenin 信号对多种细胞类型的各种细胞过程至关重要,包括成骨细胞(OB)的分化和功能。Wnt/β-catenin信号在成骨细胞中究竟是如何调控的,至今仍是个谜。ATP6AP2是V-ATP酶的一个附属亚基,在多种细胞类型/器官和多种信号通路中发挥着重要作用。然而,ATP6AP2在OB中是否以及如何调节Wnt/β-catenin信号传导和骨形成却鲜为人知。在这里,我们提供了 OB 系细胞中的 ATP6AP2 选择性地在骨小梁区域促进 OB 介导的骨形成和骨稳态的证据。有条件地敲除(CKO)OB 系细胞中的 ATP6AP2(Atp6ap2Ocn-Cre)会减少骨小梁的骨形成和骨量,但不会减少皮质骨的形成和骨量。蛋白质组学和细胞生化研究显示,ATP6AP2-KO BMSCs 和 OBs 中的 LRP6 和 N-cadherin 减少了,但骨细胞没有减少。其他体外和体内研究显示,在基础和 Wnt 刺激条件下,ATP6AP2-KO BMSCs 和 OBs 中的β-catenin 信号转导受损,而成骨细胞没有受损,但 ATP6AP2-KO 成骨细胞中的 LRP5 减少,而 BMSCs 没有减少。进一步的细胞生物学研究发现,成骨细胞的 ATP6AP2 不是 Wnt3a 抑制β-catenin 磷酸化所必需的,但对于 LRP6/β-catenin 和 N-cadherin/β-catenin 蛋白复合物在细胞膜上的分布是必要的,从而阻止了它们的降解。表达活性β-catenin可减少ATP6AP2-KO BMSCs的OB分化缺陷。综上所述,这些结果支持了 ATP6AP2 是 LRP6 和 N-cadherin 蛋白运输和稳定性的关键调节因子的观点,从而调节了 β-catenin 的水平,证明了成骨细胞 ATP6AP2 在促进 Wnt/LRP6/β-catenin 信号传导和骨小梁形成方面具有尚未被认识的功能。
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ATP6AP2, a regulator of LRP6/β-catenin protein trafficking, promotes Wnt/β-catenin signaling and bone formation in a cell type dependent manner

Wnt/β-catenin signaling is critical for various cellular processes in multiple cell types, including osteoblast (OB) differentiation and function. Exactly how Wnt/β-catenin signaling is regulated in OBs remain elusive. ATP6AP2, an accessory subunit of V-ATPase, plays important roles in multiple cell types/organs and multiple signaling pathways. However, little is known whether and how ATP6AP2 in OBs regulates Wnt/β-catenin signaling and bone formation. Here we provide evidence for ATP6AP2 in the OB-lineage cells to promote OB-mediated bone formation and bone homeostasis selectively in the trabecular bone regions. Conditionally knocking out (CKO) ATP6AP2 in the OB-lineage cells (Atp6ap2Ocn-Cre) reduced trabecular, but not cortical, bone formation and bone mass. Proteomic and cellular biochemical studies revealed that LRP6 and N-cadherin were reduced in ATP6AP2-KO BMSCs and OBs, but not osteocytes. Additional in vitro and in vivo studies revealed impaired β-catenin signaling in ATP6AP2-KO BMSCs and OBs, but not osteocytes, under both basal and Wnt stimulated conditions, although LRP5 was decreased in ATP6AP2-KO osteocytes, but not BMSCs. Further cell biological studies uncovered that osteoblastic ATP6AP2 is not required for Wnt3a suppression of β-catenin phosphorylation, but necessary for LRP6/β-catenin and N-cadherin/β-catenin protein complex distribution at the cell membrane, thus preventing their degradation. Expression of active β-catenin diminished the OB differentiation deficit in ATP6AP2-KO BMSCs. Taken together, these results support the view for ATP6AP2 as a critical regulator of both LRP6 and N-cadherin protein trafficking and stability, and thus regulating β-catenin levels, demonstrating an un-recognized function of osteoblastic ATP6AP2 in promoting Wnt/LRP6/β-catenin signaling and trabecular bone formation.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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