羟氯喹和低抗吸收活性双膦酸盐结合物通过双重抗吸收和合成代谢作用预防和逆转卵巢切除诱导的小鼠骨丢失-动脉网

Hydroxychloroquine and a low antiresorptive activity bisphosphonate conjugate prevent and reverse ovariectomy-induced bone loss in mice through dual antiresorptive and anabolic effects

Nature 等信源发布 2024-09-05 12:36

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AbstractOsteoporosis remains incurable. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation, while the anabolic agent, teriparatide, does not inhibit bone resorption, and thus they have limited efficacy in preventing osteoporotic fractures and cause some side effects.

摘要骨质疏松症仍然无法治愈。最广泛使用的抗吸收剂双膦酸盐（BPs）也抑制骨形成，而合成代谢剂特立帕肽不抑制骨吸收，因此它们在预防骨质疏松性骨折方面的功效有限，并引起一些副作用。

Thus, there is an unmet need to develop dual antiresorptive and anabolic agents to prevent and treat osteoporosis. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation.

因此，开发双重抗吸收和合成代谢剂以预防和治疗骨质疏松症的需求尚未得到满足。用于治疗类风湿性关节炎的羟氯喹（HCQ）可防止TNF受体相关因子3（TRAF3）的溶酶体降解，TRAF3是一种NF-κB衔接蛋白，可限制骨吸收并维持骨形成。

We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects.

我们试图将HCQ与具有预期低抗吸收活性的羟基烷基BP（HABP）共价连接，以靶向将HCQ递送至骨骼，以测试这种靶向是否增加其预防骨微环境中TRAF3降解的功效，从而减少骨吸收并增加骨形成，同时减少其全身副作用。

Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections.

出乎意料的是，发现HABP-HCQ在水溶液中以盐的形式存在，由质子化的HCQ阳离子和去质子化的HABP阴离子组成。然而，它在体外抑制破骨细胞生成，刺激成骨细胞分化并增加TRAF3蛋白水平。在每天多次注射PTH的小鼠中，HABP-HCQ显着抑制破骨细胞形成和骨髓纤维化。

In contrast, HCQ inhibited marrow fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decrea.

相反，HCQ抑制骨髓纤维化，但不抑制破骨细胞的形成，而HABP单独抑制小鼠破骨细胞的形成，但不抑制纤维化。HABP-HCQ，但不是HCQ，可以预防小鼠卵巢切除术后的小梁骨丢失，重要的是，由于HABP-HCQ增加了骨形成并减少了骨质流失，因此可以增加卵巢切除小鼠的骨量。

IntroductionOsteoporosis is a major disease of aging characterized by decreased bone mass and strength, resulting in increased fracture risk. About 44 million people in the U.S. have low bone mineral density (BMD), and 10 million of them are osteoporotic.1 Elderly patients with femoral neck fractures develop serious complications, including pneumonia and deep vein thrombosis due to prolonged bed rest, and up to 20% of them die within the 12 months after the fracture.2Osteoporosis is caused by imbalanced bone remodeling, due to enhanced bone resorption and relatively reduced bone formation, mediated by osteoclasts (OCs) and osteoblasts (OBs) respectively.1 Both antiresorptive and anabolic agents are available, but they do not satisfactorily treat osteoporosis.

引言骨质疏松症是一种主要的衰老疾病，其特征是骨量和强度降低，导致骨折风险增加。美国约有4400万人骨密度（BMD）低，其中1000万人患有骨质疏松症。1老年股骨颈骨折患者会出现严重并发症，包括因长期卧床休息引起的肺炎和深静脉血栓形成，其中高达20%的人在骨折后12个月内死亡。2骨质疏松症是由骨重建不平衡引起的，这是由于骨吸收增强和骨形成相对减少，分别由破骨细胞（OC）和成骨细胞（OB）介导。1抗吸收和合成代谢剂都可用，但它们不能令人满意地治疗骨质疏松症。

For example, the antiresorptive agents, bisphosphonates (BPs) and the RANKL monoclonal antibody, denosumab, also inhibit bone formation,3,4 but they reduce the rate of osteoporotic fracture by only ~50%5 and a small percentage of patients also develop osteonecrosis of the jaw or atypical femoral shaft fractures.6 In addition, following discontinuation of denosumab some patients have vertebral fractures due to rebound increased bone resorption.7,8 Furthermore, treatment with the anabolic agent, teriparatide, is limited to two years due to safety concerns,9,10,11,12 and is typically followed by treatment with antiresorptive agents,13 because their anabolic effects are transient, and discontinuation results in increased bone resorption.14 In addition, combination therapy with teriparatide and a BP does not appear to offer advantages over the use of either agent alone.15,16 Similarly, switching from alendronate to teriparatide does not improve hip BMD, although addition of an anabolic agent to ongoing alendronate treat.

例如，抗吸收剂双膦酸盐（BPs）和RANKL单克隆抗体denosumab也能抑制骨形成[3,4]，但它们仅使骨质疏松性骨折的发生率降低约50%[5]，一小部分患者也会发生颌骨坏死或非典型股骨干骨折[6]。此外，停用denosumab后，一些患者由于反弹增加了骨吸收而出现椎骨骨折[7,8]。此外，由于安全问题，使用合成代谢剂特立帕肽治疗仅限于两年[9,10,11,12]，通常随后使用抗吸收剂治疗[13]，因为他们的合成代谢作用是短暂的，停药会导致骨吸收增加[14]。此外，与单独使用任何一种药物相比，特立帕肽和BP的联合治疗似乎都没有优势[15,16]。同样，从阿仑膦酸钠转换为特立帕肽并不能改善髋关节BMD，尽管在正在进行的阿仑膦酸盐治疗中添加了合成代谢剂。

Data availability

数据可用性

All data are available in the main text or as supplementary materials.

所有数据均可在正文或补充材料中找到。

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Download referencesAcknowledgementsThe authors sincerely thank Lindsay Schnur for micro-CT imaging and analysis, and the Core Services from Center for Musculoskeletal Research (CMSR) (NIH/NIAMS P30 AR069655), University of Rochester Medical Center.FundingThis study was funded by National Institutes of Health, National Institute on Aging, grant numbers, R01AG076731, R01AG049994, and National Institute for Arthritis and Musculoskeletal and Skin Diseases, R01AR043510, and P30 AR069655.

下载参考文献致谢作者衷心感谢Lindsay Schnur的显微CT成像和分析，以及罗切斯特大学医学中心肌肉骨骼研究中心（CMSR）（NIH/NIAMS P30 AR069655）的核心服务。资助这项研究由美国国立卫生研究院，美国国立衰老研究所，资助号R01AG076731，R01AG049994，美国国立关节炎和肌肉骨骼与皮肤病研究所R01AR043510和P30 AR069655资助。

The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.Author informationAuthors and AffiliationsDepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USAZhenqiang Yao, Akram Ayoub, Jun Wu, Churou Tang, Rong Duan, Lianping Xing & Brendan F.

内容完全由作者负责，不一定代表资助机构的官方观点。作者信息作者和附属机构罗切斯特大学医学中心病理学和检验医学系，纽约州罗切斯特，14642，美国姚振强，阿克兰·阿尤布，吴军，唐楚柔，段荣，邢连平和布伦丹。

BoyceDepartment of Chemistry, University of Rochester, Rochester, NY14627, USAVenkatesan Srinivasan, Aleksa Milosavljevic, Frank H. Ebetino & Alison J. FrontierSchool of Arts and Sciences, University of Rochester, Rochester, NY14627, USAChurou TangBioVinc, LLC, Pasadena, CA, 91107, USAFrank H. EbetinoAuthorsZhenqiang YaoView author publicationsYou can also search for this author in.

男孩罗切斯特大学化学系，罗切斯特，NY14627，USAVenkatesan Srinivasan，Aleksa Milosavljevic，Frank H.Ebetino＆Alison J.FrontierSchool of Arts and Sciences，Rochester，NY14627，USAChurou TangBioVinc，LLC，Pasadena，CA，91107，USAFrank H.Ebetinouthorszhenqiang YaoView作者出版物你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsConceptualization: ZY, LX, FHE, BFB. Methodology: ZY, AA, JW, CT, RD, AM, FHE, AF. Investigation: AA, JW, CT, RD, AM, FHE, AF, ZY. Funding acquisition: ZY, BFB. Writing – original draft: ZY. Writing – review & editing: ZY, BFB, FHE, AFCorresponding authorsCorrespondence to.

PubMed谷歌学术贡献概念：ZY，LX，FHE，BFB。方法学：ZY，AA，JW，CT，RD，AM，FHE，AF。调查：AA，JW，CT，RD，AM，FHE，AF，ZY。资金获取：ZY，BFB。写作-原稿：ZY。写作-评论和编辑：ZY，BFB，FHE，AF通讯作者通讯。

Zhenqiang Yao or Brendan F. Boyce.Ethics declarations

姚振强或布伦丹·F·博伊斯。道德宣言

Competing interests

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The authors declare no competing interests.

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Ethics approval and consent to participate

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All experimental protocols were approved by the University of Rochester Committee for Animal Resources. All methods were carried out in accordance with the American Veterinary Medical Association (AVMA) guidelines and regulations.

所有实验方案均经罗切斯特大学动物资源委员会批准。所有方法均按照美国兽医协会（AVMA）的指南和规定进行。

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Supplementary information41413_2024_352_MOESM1_ESM.docHydroxychloroquine and a low antiresorptive activity bisphosphonate conjugate prevent and reverse ovariectomy-induced bone loss in mice through dual antiresorptive and anabolic effectsRights and permissions

补充信息41413\u 2024\u 352\u MOESM1\u ESM.docHydroxychloroquine和低抗吸收活性双膦酸盐偶联物通过双重抗吸收和合成代谢作用预防和逆转卵巢切除术引起的小鼠骨质流失权利和许可

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Reprints and permissionsAbout this articleCite this articleYao, Z., Ayoub, A., Srinivasan, V. et al. Hydroxychloroquine and a low antiresorptive activity bisphosphonate conjugate prevent and reverse ovariectomy-induced bone loss in mice through dual antiresorptive and anabolic effects.

转载和许可本文引用本文Yao，Z.，Ayoub，A.，Srinivasan，V。等人。羟氯喹和低抗吸收活性双膦酸盐缀合物通过双重抗吸收和合成代谢作用预防和逆转卵巢切除术诱导的小鼠骨质流失。

Bone Res 12, 52 (2024). https://doi.org/10.1038/s41413-024-00352-6Download citationReceived: 20 April 2024Revised: 14 June 2024Accepted: 12 July 2024Published: 05 September 2024DOI: https://doi.org/10.1038/s41413-024-00352-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

骨研究12,52（2024）。https://doi.org/10.1038/s41413-024-00352-6Download引文收到日期：2024年4月20日修订日期：2024年6月14日接受日期：2024年7月12日发布日期：2024年9月5日OI：https://doi.org/10.1038/s41413-024-00352-6Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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