Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Feng Gao, Qimiao Hu, Wenwei Chen, Jilong Li, Cheng Qi, Yiwen Yan, Cheng Qian, Mei Wan, James Ficke, Junying Zheng, Xu Cao
{"title":"Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain","authors":"Feng Gao, Qimiao Hu, Wenwei Chen, Jilong Li, Cheng Qi, Yiwen Yan, Cheng Qian, Mei Wan, James Ficke, Junying Zheng, Xu Cao","doi":"10.1038/s41413-024-00316-w","DOIUrl":null,"url":null,"abstract":"<p>Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of <i>cyclooxygenase-2 (COX2)</i> in the osteoblast lineage cells or knockout of receptor 4 (<i>EP4)</i> in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of <i>TrkA</i> in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bone Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41413-024-00316-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0

Abstract

Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of cyclooxygenase-2 (COX2) in the osteoblast lineage cells or knockout of receptor 4 (EP4) in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

Abstract Image

大脑通过 PGE2 骨骼交感神经调节负重骨骼:对踝关节骨关节炎和疼痛的影响
骨骼是一种机械敏感性组织,会不断发生重塑以适应机械负荷环境。然而,目前还不清楚骨细胞对机械应力的反应信号是否会在大脑中得到处理和解读。在这项研究中,我们发现大脑下丘脑通过感知骨前列腺素 E2(PGE2)浓度对机械负荷的反应来调节骨的重塑和结构。骨骼中的前列腺素 E2 水平与其承重成正比。当尾部悬吊小鼠的负重发生变化时,骨骼中的前列腺素 E2 浓度也会随着负重的变化而变化。成骨细胞系细胞中环氧化酶-2(COX2)的缺失或感觉神经中受体 4(EP4)的敲除会阻碍骨形成对机械负荷的反应。此外,敲除感觉神经中的 TrkA 也会显著减少机械负荷诱导的骨形成。此外,机械负荷会诱导下丘脑弓状核(ARC)中的 cAMP 响应元件结合蛋白(CREB)磷酸化,从而抑制室旁核(PVN)中交感神经酪氨酸羟化酶(TH)的表达,促进骨形成。最后,我们发现 PGE2 的升高与踝关节骨关节炎(AOA)和疼痛有关。总之,我们的数据表明,在对机械负荷做出反应时,骨骼会以下丘脑处理 PGE2 驱动的外周信号的形式进行互感,以维持骨的生理平衡,而长期升高的 PGE2 可在 AOA 期间被感知为疼痛,并对潜在的治疗产生影响。
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
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.
×
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:481959085
Book学术官方微信