Protein kinase A is a dependent factor and therapeutic target in mouse models of fibrous dysplasia.

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Zhongyu Liu, Lu Xing, Wenlong Huang, Ning Ji, Hang Zhao, Qianming Chen, Xianglong Han, Ding Bai, Xuefeng Zhao
{"title":"Protein kinase A is a dependent factor and therapeutic target in mouse models of fibrous dysplasia.","authors":"Zhongyu Liu, Lu Xing, Wenlong Huang, Ning Ji, Hang Zhao, Qianming Chen, Xianglong Han, Ding Bai, Xuefeng Zhao","doi":"10.1038/s41467-025-61402-z","DOIUrl":null,"url":null,"abstract":"<p><p>Fibrous dysplasia is a skeletal disorder caused by activating mutations in Gα<sub>s</sub>, leading to bone fractures, deformities, and pain. Protein kinase A (PKA), the principal effector of Gα<sub>s</sub>, plays critical roles in various biological processes. However, its role in fibrous dysplasia is unknown. Here we demonstrate that PKA activation replicates fibrous dysplasia-like lesions in a transgenic mouse model expressing an activating mutation of PKA in the skeletal stem cell lineage. Mechanistically, PKA promotes osteoclastogenesis and aberrant osteogenic differentiation and proliferation of skeletal stem cells, while impairing mineralization. Downregulating PKA activity, using either a genetically engineered PKA inhibitor peptide or small-molecule inhibitors, effectively alleviates fibrous dysplasia lesions in a fibrous dysplasia mouse model and safeguards bone structure by increasing trabecular bone volume in a PKA-inhibition mouse model. Although long-term pharmacological PKA inhibition remains untested, these findings demonstrate that PKA is a dependent factor in fibrous dysplasia initiation and progression, underscoring its potential as a therapeutic target.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"16 1","pages":"5425"},"PeriodicalIF":15.7000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219623/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-61402-z","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Fibrous dysplasia is a skeletal disorder caused by activating mutations in Gαs, leading to bone fractures, deformities, and pain. Protein kinase A (PKA), the principal effector of Gαs, plays critical roles in various biological processes. However, its role in fibrous dysplasia is unknown. Here we demonstrate that PKA activation replicates fibrous dysplasia-like lesions in a transgenic mouse model expressing an activating mutation of PKA in the skeletal stem cell lineage. Mechanistically, PKA promotes osteoclastogenesis and aberrant osteogenic differentiation and proliferation of skeletal stem cells, while impairing mineralization. Downregulating PKA activity, using either a genetically engineered PKA inhibitor peptide or small-molecule inhibitors, effectively alleviates fibrous dysplasia lesions in a fibrous dysplasia mouse model and safeguards bone structure by increasing trabecular bone volume in a PKA-inhibition mouse model. Although long-term pharmacological PKA inhibition remains untested, these findings demonstrate that PKA is a dependent factor in fibrous dysplasia initiation and progression, underscoring its potential as a therapeutic target.

蛋白激酶A是纤维结构不良小鼠模型的依赖因子和治疗靶点。
纤维发育不良是一种由Gαs激活突变引起的骨骼疾病,可导致骨折、畸形和疼痛。蛋白激酶A (PKA)是Gαs的主要效应体,在多种生物过程中发挥重要作用。然而,其在纤维结构不良中的作用尚不清楚。在这里,我们证明了PKA激活在骨骼干细胞谱系中表达PKA激活突变的转基因小鼠模型中复制纤维性发育不良样病变。在机制上,PKA促进骨干细胞的破骨细胞发生和异常成骨分化和增殖,同时损害矿化。使用基因工程PKA抑制剂肽或小分子抑制剂下调PKA活性,可有效缓解纤维结构不良小鼠模型中的纤维结构不良病变,并通过增加PKA抑制小鼠模型中的小梁骨体积来保护骨骼结构。尽管PKA的长期药理抑制作用尚未得到验证,但这些发现表明PKA是纤维发育不良起始和进展的依赖因素,强调了其作为治疗靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信