Osteoclasts Regulate Osteocyte Viability and Function

破骨细胞调节骨细胞的活力和功能

基本信息

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
项目类别：
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

项目摘要

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人有衰弱的裂缝风险，从而增加发病率的风险死亡。骨细胞占骨骼的95％，越来越多地被认为是骨体内平衡。随着年龄的增长，骨细胞密度降低，骨细胞的选择性缺失导致骨质疏松症。这表明保持骨细胞的生存能力和功能可能是一个有效的策略减轻与年龄有关的骨质流失。骨细胞众所周知，可以调节骨细胞。但是，潜力骨细胞对骨细胞的影响尚未评估。初步数据表明有受损的小鼠破骨细胞TGF-信号暴露于体内的骨细胞凋亡增加，而TGF-处理过的骨细胞条件培养基可保护骨细胞免受地塞米松诱导的体外凋亡。破骨细胞的作用在促进骨细胞的生存力和/或功能时，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疗法的重要意义。这这项五年职业发展应用的总体目标是检验以下假设。破骨细胞诱导旁分泌因子的产生，从而促进维持骨细胞的生存能力骨骼稳态。具体而言，我将完成与小鼠中骨细胞表型的表征破骨细胞TGF-信号传导受损并评估破骨细胞中TGF-信号的机制在体外和体内促进骨细胞生存力。其次，我将评估破骨细胞的效果通过遗传（小鼠）和药物学（人类）对小鼠和人类骨细胞的消融/耗竭方法。该提案为骨细胞表型技术提供了重要的培训机会，包括酸蚀刻/扫描电子显微镜，分析骨细胞对体内轴向的功能反应负载以及无体外培养的骨细胞基因表达的直接分析。另外，学习破骨细胞的药物耗竭对人类骨细胞的影响提供了价值经验临床机械研究。将动物研究结果与人类相关联，对于推进基本诊所的发现。因此，拟议的研究将为我提供对我职业生涯必不可少的培训开发并为开发独立的R01应用程序奠定了基础工作。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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