Plectin promotes bone formation via phase separation and sequestering annexin A2.

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-10-03 DOI:10.1016/j.bcp.2025.117403

Kaiyuan Zheng, Xi He, Yang Yu, Meng Deng, Lulu Chen, Wenwen Zhou, Dan Xia, Peihong Su, Ye Tian, Lijuan Zhang, Jing Wen, Beilei Zeng, Xiaolan Guo, Qi Liang, Bin Guo, Guangrong Wang, Yinxu Wang, Qing Wu, Li Jiao, Airong Qian, Chong Yin

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引用次数: 0

Abstract

Osteoporosis constitutes an emergent threat to human health, which partially caused by impaired osteoblast differentiation. Liquid-liquid phase separation (LLPS) is a cytophysiological process that regulates osteoblast differentiation. The plakin family, ubiquitously expressed in osteoblasts, interacts with multiple proteins and may mediate phase separation. However, limited reports exist regarding the involvement of the plakin family phase separation and osteoblast differentiation. In this study, we demonstrated that plectin (Plec), a plakin family member, enhances osteoblast differentiation and bone formation via its phase separation. This process is mediated by plectin's intrinsically disordered region (IDR). Mechanistically, plectin promotes osteoblast differentiation by sequestering annexin A2 (Anxa2), an osteoblast differentiation promoter, through phase separation. Furthermore, the functional amino acid region (aa 1967-2185) of plectin exhibited therapeutic effect in mice with osteoporosis. Our findings reveal a novel regulatory mechanism by which cytoskeletal linker proteins govern osteoblast differentiation and propose a potential therapeutic strategy for osteoporosis.

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粘附素通过相分离和隔离膜联蛋白A2促进骨形成。

骨质疏松症是对人类健康的一种紧迫威胁，部分原因是成骨细胞分化受损。液-液相分离（LLPS）是调控成骨细胞分化的细胞生理过程。plakin家族在成骨细胞中普遍表达，与多种蛋白相互作用，并可能介导相分离。然而，关于plakin家族阶段分离和成骨细胞分化的参与报道有限。在这项研究中，我们证明了plakin家族成员plectin （Plec）通过相分离促进成骨细胞分化和骨形成。这一过程由plectin's intrinsic disordered region （IDR）介导。从机制上讲，粘连素通过相分离分离膜联蛋白A2 （Anxa2）促进成骨细胞分化。此外，plectin的功能氨基酸区（aa 1967-2185）对小鼠骨质疏松症有治疗作用。我们的发现揭示了细胞骨架连接蛋白调控成骨细胞分化的一种新的调控机制，并提出了一种潜在的骨质疏松症治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.