Osteoclasts Regulate Osteocyte Viability and Function

破骨细胞调节骨细胞的活力和功能

• 批准号: 10017654
• 负责人: Megan M Weivoda
• 金额: $ 10.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017654
• 关键词: Ablation; Acids; Adult; Affect; Age; Age-Related Bone Loss; American; Animals; Apoptosis; Biology; Bone Marrow; Bone Matrix; Bone Resorption; Chemicals; Clinic; Clinical; Clinical Research; Coupling; Data; Development; Dexamethasone; Disease; Evaluation; Exhibits; Fracture; Gene Expression; Genetic; Genetic Models; Glucocorticoids; Goals; Homeostasis; Human; Impact evaluation; Impairment; In Vitro; Individual; Mechanics; Mediating; Mentors; Methods; Morbidity - disease rate; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Pharmacology; Phenocopy; Phenotype; Plasma; Production; Research; Research Personnel; Risk; Role; Scanning Electron Microscopy; Signal Transduction; Skeleton; Techniques; Testing; Training; Transforming Growth Factor beta; WNT Signaling Pathway; Work; aging population; bone; bone loss; bone mass; bone preservation; career development; cathepsin K; cell type; cost; density; expectation; experience; in vivo; inhibitor/antagonist; innovation; mechanical load; mortality; mouse model; novel; osteoporosis with pathological fracture; paracrine; prevent; promoter; public health relevance; response; skeletal; tibia; training opportunity

Abstract Age-related bone loss puts individuals at risk for debilitating fractures that increase the risk for morbidity and mortality. Osteocytes make up 95% of the skeleton and are increasingly recognized as master regulators of bone homeostasis. With age there is reduced osteocyte density, and selective deletion of osteocytes results in osteoporosis. This suggests that maintaining osteocyte viability and function may be an effective strategy to mitigate age-related bone loss. Osteocytes are well-known to regulate osteoclasts; however, the potential effects of osteoclasts on osteocytes have not been evaluated. Preliminary data suggest that mice with impaired osteoclast TGF- signaling exhibit increased osteocyte apoptosis in vivo, and TGF- treated osteoclast conditioned media protects osteocytes from dexamethasone-induced apoptosis in vitro. A role for osteoclasts in promoting osteocyte viability and/or function, a relationship supported by my preliminary data, would have important implications for the majority of osteoporosis therapies that act by reducing osteoclast numbers. The overall goal of this five year career development application is to test the hypothesis that TGF-β signaling in osteoclasts induces the production of paracrine factors that promote osteocyte viability necessary to maintain skeletal homeostasis. Specifically, I will complete the characterization of the osteocyte phenotype in mice with impaired osteoclast TGF- signaling and evaluate the mechanism by which TGF- signaling in osteoclasts promotes osteocyte viability in vitro and in vivo. Secondly, I will evaluate the effect of osteoclast ablation/depletion on osteocytes in mice and humans through genetic (mouse) and pharmacologic (humans) methods. This proposal offers significant training opportunities in osteocyte phenotyping techniques, including acid etching/scanning electron microscopy, analysis of the functional response of osteocytes to in vivo axial loading, as well as direct analysis of osteocyte gene expression without in vitro culture. In addition, studying the effects of pharmacological depletion of osteoclasts on osteocytes in humans offers valuable experience in clinical mechanistic research. Correlating the results of animal studies to humans is crucial to advancing basic findings to the clinic. Therefore, the proposed studies will provide me with training essential to my career development and lay the ground work for developing an independent R01 application.

抽象的 与年龄相关的骨质流失使个体面临衰弱性骨折的风险，从而增加发病和死亡的风险 死亡。骨细胞占骨骼的 95%，并且越来越被认为是骨骼的主要调节者 骨稳态。随着年龄的增长，骨细胞密度降低，选择性删除骨细胞会导致 骨质疏松症。这表明维持骨细胞的活力和功能可能是一种有效的策略 减轻与年龄相关的骨质流失。众所周知，骨细胞可以调节破骨细胞。然而，潜在的 尚未评估破骨细胞对骨细胞的影响。初步数据表明，受损小鼠 破骨细胞 TGF-β 信号显示体内骨细胞凋亡增加，并且 TGF-β 处理的破骨细胞 条件培养基在体外保护骨细胞免受地塞米松诱导的细胞凋亡。破骨细胞的作用 在促进骨细胞活力和/或功能方面，我的初步数据支持的关系将具有 对大多数通过减少破骨细胞数量起作用的骨质疏松症治疗具有重要意义。这 这个五年职业发展申请的总体目标是检验以下假设：TGF-β 信号传导在 破骨细胞诱导产生旁分泌因子，促进维持骨细胞活力所必需的 骨骼稳态。具体来说，我将完成小鼠骨细胞表型的表征 破骨细胞 TGF-β 信号传导受损并评估破骨细胞中 TGF-β 信号传导的机制 促进体外和体内骨细胞的活力。其次，我来评估一下破骨细胞的效果 通过遗传（小鼠）和药理学（人类）消融/消耗小鼠和人类的骨细胞 方法。该提案提供了骨细胞表型分析技术的重要培训机会，包括 酸蚀/扫描电镜，分析骨细胞对体内轴的功能反应 加载以及无需体外培养即可直接分析骨细胞基因表达。此外，学习 破骨细胞的药理学耗竭对人类骨细胞的影响提供了宝贵的经验 临床机制研究。将动物研究结果与人类相关联对于推进基础研究至关重要 检查结果到诊所。因此，拟议的研究将为我提供对我的职业生涯至关重要的培训 开发并为开发独立的 R01 应用程序奠定基础。

项目成果

miRNAs in osteoclast biology.

• DOI: 10.1016/j.bone.2020.115757
• 发表时间: 2021-03
• 期刊: Bone
• 影响因子: 4.1
• 作者: Weivoda MM;Lee SK;Monroe DG
• 通讯作者: Monroe DG

Novel insights into the coupling of osteoclasts and resorption to bone formation.

• DOI: 10.1016/j.semcdb.2021.10.008
• 发表时间: 2022-03
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Durdan MM;Azaria RD;Weivoda MM
• 通讯作者: Weivoda MM

Sclerostin expression and functions beyond the osteocyte.

• DOI: 10.1016/j.bone.2016.11.024
• 发表时间: 2017-03
• 期刊: Bone
• 影响因子: 4.1
• 作者: Weivoda MM;Youssef SJ;Oursler MJ
• 通讯作者: Oursler MJ

Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice.

• DOI: 10.1002/jbmr.3351
• 发表时间: 2018-04
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Farr JN;Weivoda MM;Nicks KM;Fraser DG;Negley BA;Onken JL;Thicke BS;Ruan M;Liu H;Forrest D;Hawse JR;Khosla S;Monroe DG
• 通讯作者: Monroe DG