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
- 来源:
- 关键词:AcuteAffectAgingBiologicalBiological AvailabilityBiomechanicsBone remodelingCalciumCalcium ChannelCalmodulinCationsCell physiologyCellsCiliaConsensusCuesCultured CellsCytoskeletonDataDiseaseDown-RegulationDrug TargetingElementsEnzymesGenesGeneticGenetic TranscriptionGrantHealthHumanIn VitroIntegrinsKnockout MiceKnowledgeLinkLiquid substanceMechanical StressMechanicsMediator of activation proteinMessenger RNAMicrotubule-Associated ProteinsMicrotubulesModelingMolecularMutationNADPH OxidaseOsteocytesOsteogenesisOsteoporosisOutcomeOutcome MeasurePathway interactionsPatientsPersonsPharmacologyPhenotypePhosphotransferasesPlayPost-Translational Protein ProcessingProteinsReactive Nitrogen SpeciesReactive Oxygen SpeciesRegulationRepressionRoleSecond Messenger SystemsSignal PathwaySignal TransductionSkeletonSourceStriated MusclesStructureTestingTissuesTranslatingTubulinVanilloidWorkalpha Tubulinantagonistbasebeta cateninbonebone lossbone massbone preservationbone qualityconditional knockoutcrosslinkdefined contributiondensityeconomic impactgenetic approachimprovedin vivoin vivo Modelinsightloss of functionmechanical energymechanical loadmechanical signalmechanotransductionmutantnew therapeutic targetnovelosteogenicpreventprimary outcomereceptorresponsesensorshear stressskeletalskeletal disordertool
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.
项目总结
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.
- DOI:10.1007/s00395-020-00818-8
- 发表时间:2020-09-10
- 期刊:
- 影响因子:9.5
- 作者:
- 通讯作者:
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
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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
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{{ 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:
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