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: 10395929
• 负责人: Joseph P. Stains
• 金额: $ 33.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10395929
• 关键词: Acute; Affect; Aging; Biological; Biological Availability; Biomechanics; Bone remodeling; Calcium; Calcium Channel; Calmodulin; Cations; Cell physiology; Cells; Cilia; Consensus; Cues; Cultured Cells; Cytoskeleton; Data; Disease; Down-Regulation; Drug Targeting; Elements; Enzymes; Genes; Genetic; Genetic Transcription; Grant; Health; Human; In Vitro; Integrins; Knockout Mice; Knowledge; Link; Liquid substance; Mechanical Stress; Mechanics; Mediator of activation protein; Messenger RNA; Microtubule-Associated Proteins; Microtubules; Modeling; Molecular; Mutation; NADPH Oxidase; Osteocytes; Osteogenesis; Osteoporosis; Outcome; Outcome Measure; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Phosphotransferases; Play; Post-Translational Protein Processing; Proteins; Reactive Nitrogen Species; Reactive Oxygen Species; Regulation; Repression; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Skeleton; Source; Striated Muscles; Structure; Testing; Tissues; Translating; Tubulin; Vanilloid; Work; alpha Tubulin; antagonist; base; beta catenin; bone; bone loss; bone mass; bone preservation; bone quality; conditional knockout; crosslink; defined contribution; density; economic impact; genetic approach; improved; in vivo; in vivo Model; insight; loss of function; mechanical energy; mechanical load; mechanical signal; mechanotransduction; mutant; new therapeutic target; novel; osteogenic; prevent; primary outcome; receptor; response; sensor; shear stress; skeletal; skeletal disorder; tool

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.

项目摘要 骨质疏松症和其他骨骼脆弱性疾病影响着全世界2亿多人， 每年生产约900万件产品。预防患者的骨丢失和/或恢复丢失的骨量是 这对于限制骨骼脆弱性疾病对个人和经济的影响至关重要。一个关键目标， 新骨形成的刺激是蛋白硬化素，Wnt/β-连环蛋白信号传导的拮抗剂 级联反应，由骨包埋的骨细胞产生。许多骨合成代谢线索，包括 机械负荷，减少硬化蛋白的表达，导致成骨细胞生成的“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，将这些负载信号传递给生物效应器，这些生物效应器的身份以及如何 sclerostin生物利用度的调节尚不清楚。我们的初步数据揭示了一些新的 骨细胞如何感知和响应机械提示的介质。具体来说，我们发现微管- 依赖性细胞骨架刚度调节机械激活的Ca 2+内流。此外，我们暗示TRPV 4 作为一个主要的机械依赖性Ca 2+内流途径，驱动Ca 2+依赖性激活 钙/钙调蛋白依赖性激酶II（CamKII）以降低骨细胞中sclerostin的生物利用度。在 目前的赠款，我们将使用在体外，离体和体内模型，以确定MT密度的贡献， 细胞骨架交联对骨细胞力学传感的影响，明确骨细胞的贡献和机制 TRPV 4通道开放对机械应力的响应，并阐明了FFSS- 依赖性CamKII激活调节硬化蛋白降解和Sost基因转录。这项工作将更多 充分解释sclerostin的生物学调节，将机械地联系知识中的几个空白， 骨细胞如何感知和响应机械负荷，并将揭示新的目标，以改善或保护 骨质老化和疾病。

项目成果

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: NPJ AGING
• 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: Basic research in cardiology
• 影响因子: 9.5

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: Neuromuscular disorders : NMD
• 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: Clinical orthopaedics and related research
• 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: Frontiers in physiology
• 影响因子: 4
• 作者: Aljohani H;Senbanjo LT;Al Qranei M;Stains JP;Chellaiah MA
• 通讯作者: Chellaiah MA