Dimeric R25CPTH(1-34) activates the parathyroid hormone-1 receptor in vitro and stimulates bone formation in osteoporotic female mice.

IF 6.4 1区 生物学 Q1 BIOLOGY
eLife Pub Date : 2025-03-28 DOI:10.7554/eLife.97579
Minsoo Noh, Xiangguo Che, Xian Jin, Dong-Kyo Lee, Hyun-Ju Kim, Doo Ri Park, Soo Young Lee, Hunsang Lee, Thomas J Gardella, Je-Yong Choi, Sihoon Lee
{"title":"Dimeric <sup>R25C</sup>PTH(1-34) activates the parathyroid hormone-1 receptor in vitro and stimulates bone formation in osteoporotic female mice.","authors":"Minsoo Noh, Xiangguo Che, Xian Jin, Dong-Kyo Lee, Hyun-Ju Kim, Doo Ri Park, Soo Young Lee, Hunsang Lee, Thomas J Gardella, Je-Yong Choi, Sihoon Lee","doi":"10.7554/eLife.97579","DOIUrl":null,"url":null,"abstract":"<p><p>Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated <sup>R25C</sup>PTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that <sup>R25C</sup>PTH(1-84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, <sup>R25C</sup>PTH(1-34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric <sup>R25C</sup>PTH(1-34) induced acute calcemic and phosphaturic responses comparable to PTH(1-34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1-34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952747/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"eLife","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7554/eLife.97579","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1-84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1-34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1-34) induced acute calcemic and phosphaturic responses comparable to PTH(1-34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1-34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.

骨质疏松症以骨密度和骨强度降低为特征,会增加骨折风险、疼痛并限制活动能力。现有的甲状旁腺激素(PTH)类似物疗法能有效促进骨形成并减少严重骨质疏松症患者的骨折,但其使用受到潜在不良反应的限制。为了寻求更安全的骨质疏松症治疗方法,我们对 R25CPTH 进行了研究,这是一种 PTH 变体,其中第 25 位的原生精氨酸被半胱氨酸取代。这些研究的起因是我们发现一名甲状旁腺功能减退症患者因 R25C 基因同源突变而具有较高的骨矿物质密度,我们还探讨了它对细胞中 PTH-1 型受体(PTH1R)信号转导和小鼠骨代谢的影响。我们的研究结果表明,R25CPTH(1-84)会在细胞内和细胞外形成二聚体,合成的二聚体肽 R25CPTH(1-34) 在 PTH1R 介导的环磷酸腺苷(cAMP)反应中表现出改变的活性。给小鼠注射一次二聚 R25CPTH(1-34) 后,可诱导与 PTH(1-34) 相当的急性血钙和磷酸盐反应。此外,每天重复注射可增加完整小鼠的钙质骨厚度,改善卵巢切除(OVX)小鼠的骨小梁和皮质骨参数,与 PTH(1-34) 相似。总体结果表明,二聚 PTH 肽配体在体外和体内都能像 PTH 一样激活 PTH1R,这为开发治疗性 PTH 类似物提供了一条潜在的途径。
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
eLife
eLife BIOLOGY-
CiteScore
12.90
自引率
3.90%
发文量
3122
审稿时长
17 weeks
期刊介绍: eLife is a distinguished, not-for-profit, peer-reviewed open access scientific journal that specializes in the fields of biomedical and life sciences. eLife is known for its selective publication process, which includes a variety of article types such as: Research Articles: Detailed reports of original research findings. Short Reports: Concise presentations of significant findings that do not warrant a full-length research article. Tools and Resources: Descriptions of new tools, technologies, or resources that facilitate scientific research. Research Advances: Brief reports on significant scientific advancements that have immediate implications for the field. Scientific Correspondence: Short communications that comment on or provide additional information related to published articles. Review Articles: Comprehensive overviews of a specific topic or field within the life sciences.
×
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