RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Luis F. de Castro, Jarred M. Whitlock, Zachary Michel, Kristen Pan, Jocelyn Taylor, Vivian Szymczuk, Brendan Boyce, Daniel Martin, Vardit Kram, Rebeca Galisteo, Kamran Melikov, Leonid V. Chernomordik, Michael T. Collins, Alison M. Boyce
{"title":"RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia","authors":"Luis F. de Castro, Jarred M. Whitlock, Zachary Michel, Kristen Pan, Jocelyn Taylor, Vivian Szymczuk, Brendan Boyce, Daniel Martin, Vardit Kram, Rebeca Galisteo, Kamran Melikov, Leonid V. Chernomordik, Michael T. Collins, Alison M. Boyce","doi":"10.1038/s41413-023-00311-7","DOIUrl":null,"url":null,"abstract":"<p>Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gα<sub>s</sub> variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.</p><p>TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2024-02-20","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/s41413-023-00311-7","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

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191

Abstract Image

抑制 RANKL 可降低纤维发育不良的病变细胞性和 Gαs 变异表达,并促进成骨成熟
纤维发育不良(FD)是一种罕见的致残性骨骼疾病,目前尚无成熟的治疗方法。越来越多的证据表明,抑制破骨细胞生成因子核卡巴-B配体受体激活剂(RANKL)是一种潜在的治疗策略。在本研究中,我们通过评估在地诺单抗(NCT03571191)2 期临床试验中治疗前后的人类 FD 组织以及小鼠体内和体外临床前模型,研究了抑制 FD 组织中 RANKL 的机制及其对骨生成细胞可能产生的间接影响。对人类和小鼠组织的组织学分析表明,RANKL抑制后,FD病变中的成骨成熟度增加、细胞减少、致病性Gαs变体表达降低。人和小鼠组织的 RNA 测序也支持这些发现。在体内外病变模型中进一步评估了破骨细胞与突变型成骨细胞之间的相互作用,结果表明异常FD成骨细胞的增殖依赖于破骨细胞。这项研究的结果表明,除预期的抗破骨细胞作用外,地诺单抗还能通过减少 FD 细胞增殖和增加成骨细胞成熟来降低 FD 病变活性,从而增加病变内的骨形成。这些发现凸显了破骨细胞和前成骨细胞/成骨细胞之间的细胞串扰作为 FD 病理学驱动因素所起的未被重视的作用,并证明了地诺单抗治疗骨病的一种新的作用机制。
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