Mechanisms of osteocyte mechano-signaling and sclerostin regulation

骨细胞机械信号传导和硬化素调节机制

基本信息

  • 批准号:
    10395929
  • 负责人:
  • 金额:
    $ 33.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-03-21 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Osteoporosis and other diseases of skeletal fragility affect more than 200 million people worldwide and contributes to ~9 million factures annually. Preventing bone loss and/or restoring lost bone mass in patients is of vital importance to limiting the personal and economic impact of diseases of skeletal fragility. A key target in the stimulation of new bone formation is the protein sclerostin, an antagonist of the Wnt/beta-catenin signaling cascade, which is produced by bone embedded osteocytes. Numerous osteoanabolic cues, including mechanical load, reduce expression of the sclerostin leading to “de-repression” of osteoblastogenesis and stimulation of de novo bone formation. However, key mechanistic details of how osteocytes sense mechanical load, transduce these load signals to biologic effectors, the identity of these biological effectors and how sclerostin bioavailability is regulated are unclear. Our preliminary data have uncovered a number of novel mediators of how osteocytes sense and respond to mechanical cues. Specifically, we show that microtubule- dependent cytoskeletal stiffness regulates mechano-activated Ca2+ influx. Furthermore, we implicate TRPV4 as a major mechano-dependent Ca2+ influx pathway that drives Ca2+ dependent activation of calcium/calmodulin-dependent kinase II (CamKII) to reduce sclerostin bioavailability in the osteocyte. In the present grant, we will use in vitro, ex vivo and in vivo models to determine the contribution of MT density and cytoskeletal crosslinking to osteocyte mechanosensing, define the contribution and mechanisms of osteocyte TRPV4 channel opening in response to mechanical stress and elucidate the mechanisms by which FFSS- dependent CamKII activation regulates sclerostin degradation and Sost gene transcription. This work will more fully explain the biological regulation of sclerostin, will mechanistically link several gaps in the knowledge of how osteocytes sense and respond to mechanical load, and will reveal novel targets to improve or preserve bone mass in aging and disease.
项目概要 骨质疏松症和其他骨骼脆弱疾病影响着全世界 2 亿多人 每年贡献约 900 万个工厂。预防骨质流失和/或恢复患者流失的骨量是 对于限制骨骼脆弱疾病对个人和经济的影响至关重要。一个关键目标 刺激新骨形成的是蛋白质硬化蛋白,它是 Wnt/β-连环蛋白信号传导的拮抗剂 级联,由嵌入骨的骨细胞产生。许多骨合成代谢线索,包括 机械负荷,减少硬化蛋白的表达,导致成骨细胞生成“去抑制” 刺激从头骨形成。然而,骨细胞如何感知机械的关键机制细节 负载,将这些负载信号转导至生物效应器,这些生物效应器的身份以及如何 硬化素生物利用度的调节尚不清楚。我们的初步数据发现了一些新颖的 骨细胞如何感知和响应机械信号的介质。具体来说,我们表明微管- 依赖的细胞骨架刚度调节机械激活的 Ca2+ 流入。此外,我们还暗示TRPV4 作为主要的机械依赖性 Ca2+ 流入途径,驱动 Ca2+ 依赖性激活 钙/钙调蛋白依赖性激酶 II (CamKII) 可降低骨细胞中硬化素的生物利用度。在 目前的资助,我们将使用体外、离体和体内模型来确定 MT 密度和 细胞骨架交联与骨细胞机械传感,定义骨细胞的贡献和机制 TRPV4 通道响应机械应力而打开,并阐明 FFSS- 的机制 依赖的 CamKII 激活调节硬化蛋白降解和 Sost 基因转录。这项工作将更加 充分解释硬化蛋白的生物调节,将机械地连接几个知识空白 骨细胞如何感知和响应机械负荷,并将揭示改善或保持的新目标 衰老和疾病中的骨量。

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice.
  • DOI:
    10.1038/s41514-022-00089-8
  • 发表时间:
    2022-06-27
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bernier, Michel;Enamorado, Ignacio Navas;Gomez-Cabrera, Mari Carmen;Calvo-Rubio, Miguel;Gonzalez-Reyes, Jose Antonio;Price, Nathan L;Cortes-Rodriguez, Ana Belen;Rodriguez-Aguilera, Juan Carlos;Rodriguez-Lopez, Sandra;Mitchell, Sarah J;Murt, Kelsey N;Kalafut, Krystle;Williams, Katrina M;Ward, Christopher W;Stains, Joseph P;Brea-Calvo, Gloria;Villalba, Jose M;Cortassa, Sonia;Aon, Miguel A;de Cabo, Rafael
  • 通讯作者:
    de Cabo, Rafael
Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia.
GsMTx4-D provides protection to the D2.mdx mouse.
  • DOI:
    10.1016/j.nmd.2018.07.005
  • 发表时间:
    2018-10
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ward CW;Sachs F;Bush ED;Suchyna TM
  • 通讯作者:
    Suchyna TM
Failure of Indomethacin and Radiation to Prevent Blast-induced Heterotopic Ossification in a Sprague-Dawley Rat Model.
吲哚美辛和辐射未能防止 Sprague-Dawley 大鼠模型中爆炸诱导的异位骨化。
  • DOI:
    10.1097/corr.0000000000000594
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Robertson,AstorD;Chiaramonti,AlexanderM;Nguyen,ThaoP;Jaffe,DavidE;Holmes,RobertE;Hanna,ELex;Rhee,JuongG;Barfield,WilliamR;Fourney,WilliamB;Stains,JosephP;Pellegrini,VincentD
  • 通讯作者:
    Pellegrini,VincentD
Methylsulfonylmethane Increases the Alveolar Bone Density of Mandibles in Aging Female Mice.
  • DOI:
    10.3389/fphys.2021.708905
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Aljohani H;Senbanjo LT;Al Qranei M;Stains JP;Chellaiah MA
  • 通讯作者:
    Chellaiah MA
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Joseph P. Stains其他文献

Characterization of a pollen-expressed gene encoding a putative pectin esterase ofPetunia inflata
  • DOI:
    10.1007/bf00043881
  • 发表时间:
    1994-06-01
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Jing-Hong Mu;Joseph P. Stains;Teh-hui Kao
  • 通讯作者:
    Teh-hui Kao
Microtubule Remodeling Contributes to the Loss of Force and Power in Aging Skeletal Muscle
  • DOI:
    10.1016/j.bpj.2019.11.2740
  • 发表时间:
    2020-02-07
  • 期刊:
  • 影响因子:
  • 作者:
    Humberto Cavalcante Joca;Anicca Harriot;Jenna Leser;Andrew Coleman;Guoli Shi;Joseph P. Stains;Christopher W. Ward
  • 通讯作者:
    Christopher W. Ward
Microtubule Mechanotransduction through Nox2-ROS Initiates TRPV4 Calcium Influx and Purinergic Calcium Oscillations that Regulate Osteocyte Mechano-Sensing
  • DOI:
    10.1016/j.bpj.2018.11.2041
  • 发表时间:
    2019-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Katrina M. Williams;Nicole Gould;Derek Jones;Ramzi Khairallah;Christopher W. Ward;Joseph P. Stains
  • 通讯作者:
    Joseph P. Stains
Increased Microtubule Density and Level of Detyrosination Occur Coincident with Sarcomere Malformations in Diseased and Aging Skeletal Muscle
  • DOI:
    10.1016/j.bpj.2018.11.2188
  • 发表时间:
    2019-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Anicca Harriot;Andrew Coleman;Shama R. Iyer;Camilo Venagas;Guoli Shi;Richard M. Lovering;Humberto C. Joca;Joseph P. Stains;Chris W. Ward
  • 通讯作者:
    Chris W. Ward

Joseph P. Stains的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Joseph P. Stains', 18)}}的其他基金

Mechanisms of osteocyte mechano-signaling and sclerostin regulation
骨细胞机械信号传导和硬化素调节机制
  • 批准号:
    9922216
  • 财政年份:
    2018
  • 资助金额:
    $ 33.65万
  • 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
  • 批准号:
    9230816
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP
间隙连接通讯 cAMP 对骨重塑的空间控制
  • 批准号:
    10586047
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
  • 批准号:
    8415654
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP
间隙连接通讯 cAMP 对骨重塑的空间控制
  • 批准号:
    9893064
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Spatial Control of Bone Remodeling by Gap Junction-Communicated cAMP
间隙连接通讯 cAMP 对骨重塑的空间控制
  • 批准号:
    10358565
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
  • 批准号:
    8628047
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
  • 批准号:
    8828565
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Regulation of Osteoblast Differentiation and Function by Connexin 43
连接蛋白 43 对成骨细胞分化和功能的调节
  • 批准号:
    9022410
  • 财政年份:
    2013
  • 资助金额:
    $ 33.65万
  • 项目类别:
Intercellular Signaling in Bone
骨中的细胞间信号传导
  • 批准号:
    7385084
  • 财政年份:
    2006
  • 资助金额:
    $ 33.65万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 33.65万
  • 项目类别:
Parkinson's disease and aging affect neural activation during continuous gait alterations to the split-belt treadmill: An [18F] FDG PET Study.
帕金森病和衰老会影响分体带跑步机连续步态改变期间的神经激活:[18F] FDG PET 研究。
  • 批准号:
    400097
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
The elucidation of the mechanism by which intestinal epithelial cells affect impaired glucose tolerance during aging
阐明衰老过程中肠上皮细胞影响糖耐量受损的机制
  • 批准号:
    19K09017
  • 财政年份:
    2019
  • 资助金额:
    $ 33.65万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Does aging of osteocytes adversely affect bone metabolism?
骨细胞老化会对骨代谢产生不利影响吗?
  • 批准号:
    18K09531
  • 财政年份:
    2018
  • 资助金额:
    $ 33.65万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Links between affect, executive function, and prefrontal structure in aging: A longitudinal analysis
衰老过程中情感、执行功能和前额叶结构之间的联系:纵向分析
  • 批准号:
    9766994
  • 财政年份:
    2018
  • 资助金额:
    $ 33.65万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 33.65万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 33.65万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 33.65万
  • 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
  • 批准号:
    9925164
  • 财政年份:
    2016
  • 资助金额:
    $ 33.65万
  • 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
  • 批准号:
    9345997
  • 财政年份:
    2016
  • 资助金额:
    $ 33.65万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了