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The Role of Reactive Oxygen Species in Osteocyte Mechano-Transduction and Sclerostin Regulation

活性氧在骨细胞机械传导和硬化素调节中的作用

基本信息

批准号：
10228399
负责人：
Nicole R. Gould
金额：
$ 3.42万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228399
关键词：
Address Adenoviruses Affect Age Aging Animal Model Astronauts Bone Development Breeding Calcium Calmodulin Catalytic Domain Cells Data Development Elderly Environment Enzyme-Linked Immunosorbent Assay Future Genes Genetic Models Genotype Health Histology Human Image Impairment In Vitro Individual Knowledge Lead Lifting Liquid substance Mechanical Stress Mechanics Mediating Methods Microgravity Microtubules Modeling Molecular Genetics Mus NADPH Oxidase Names Nature Osteoblasts Osteocalcin Osteocytes Osteogenesis Paralysed Pathway interactions Phenotype Phosphotransferases Physiology Population Production Property Reactive Oxygen Species Regulation Research Role Signal Pathway Signal Transduction Space Flight Structure Techniques Testing Therapeutic Training Vanilloid Western Blotting Work bone bone loss bone mass bone quality career design experimental study fracture risk improved in vivo in vivo Model mechanical load mechanotransduction microCT new therapeutic target novel prevent receptor response sedentary shear stress skeletal therapeutic target tomography

项目摘要

ABSTRACT The development of low bone mass caused by aging, disuse due to paralysis, or extended space flights impacts many individuals of all ages. Current therapeutics aim to slow the loss of bone mass, but none currently target the lack of mechanical loading that leads to declining bone mass in these situations. We have recently described a novel pathway in vitro in which NADPH Oxidase 2 (NOX2) produces reactive oxygen species following the onset of fluid shear stress that, in turn, activates transient receptor potential vanilloid 4 (TRPV4) channels to allow for calcium influx. This ultimately results in calcium/calmodulin-dependent kinase II (CaMKII) activation and sclerostin degradation, lifting the inhibition on osteoblasts to allow for bone formation. Though the mechano- transduction cascade controlling sclerostin abundance has been described in in vitro osteocytes, the fidelity and impact of this signaling pathway's impact on sclerostin regulation and bone mass has not been examined in vivo. This proposal will examine how the loss of NOX2, a necessary early step in the mechano-transduction cascade, affects bone quality, both in unstimulated and mechanically-stimulated conditions, in an in vivo animal model. Supported by in vitro and in vivo preliminary data, we hypothesize that the mechano-transduction pathway controlling sclerostin in vitro is conserved in vivo and that disrupting NOX2-dependent ROS production will affect basal bone properties and impair bone acquisition in response to mechanical load. We will address this hypothesis in one aim with three independent experiments: (1) Examine how NOX2 deletion in osteocytes impacts basal bone properties and mechano-responsiveness in vivo. Given the in vitro nature of our prior work on this pathway, the contribution of this mechano-transduction pathway to in vivo bone mechano-responsiveness remained unresolved. To extend these in vitro findings, this proposal will use in vitro and in vivo models, specifically a conditional deletion model, to address several knowledge gaps, including the cell autonomous role of NOX2 in osteocytes and the contribution of NOX2-mediated ROS to skeletal physiology and function. This proposal will validate novel therapeutic targets, such as ROS production, which can be exploited to mimic load in populations where traditional mechanical load is not possible.

摘要