microRNA regulation of osteocyte metabolism in bone remodeling

骨重塑中骨细胞代谢的microRNA调控

• 批准号: 10403427
• 负责人: Jihee Yoon
• 金额: $ 5.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403427
• 关键词: Acids; Biological Process; Bone Diseases; Bone Matrix; Bone remodeling; Cell physiology; Cells; Complex; Coupled; Data; Defect; Deposition; Development; Disease; Fracture; Genes; Goals; Health; Histology; Homeostasis; Knockout Mice; Maintenance; Mediating; Metabolic; Metabolic Bone Diseases; Metabolism; MicroRNAs; Mitochondria; Modeling; Molecular; Mus; Oranges; Osteoblasts; Osteoclasts; Osteocytes; Pathway interactions; Peptide Hydrolases; Play; Post-Transcriptional Regulation; Process; Property; Publishing; Regulation; Regulator Genes; Role; Series; Signal Transduction; Skeleton; Solid; TNFSF11 gene; Testing; Tissues; Transforming Growth Factor beta; Untranslated RNA; Work; base; bone; bone fracture repair; bone mass; bone quality; craniofacial; differential expression; gene function; gene network; in silico; in vitro Assay; in vivo; innovation; insight; microCT; mitochondrial dysfunction; mouse model; new therapeutic target; novel; novel therapeutics; osteogenic; overexpression; prevent; skeletal disorder; transcriptome sequencing

Matrix turnover in bone occurs through bone remodeling and is essential to maintaining bone homeostasis and health. Osteocytes, which are cells embedded in the bone matrix, regulate bone remodeling both directly by controlling the activity of osteoblasts and osteoclasts and indirectly through perilacunar/canalicular remodeling (PLR). The ability of osteocytes to regulate osteoblast and osteoclast activity in bone remodeling and homeostasis is well known, but many questions remain about the direct role of osteocyte in remodeling via PLR in bone homeostasis or disease states. In PLR, osteocytes directly resorb and deposit bone matrix surrounding their lacuno-canalicular network (LCN). Indeed, osteocyte-intrinsic deletion of TGFβ signaling in TβRIIocy−/− mice causes defective PLR and bone quality. Furthermore, preliminary data from RNAseq of TβRIIocy−/− bone shows significant mitochondrial dysfunction. However, the underlying molecular mechanism of how TGFβ regulates mitochondrial function and PLR in osteocytes is currently poorly understood. One of the most well-known molecular regulators of mitochondrial function and metabolism in other cell/tissue types is microRNAs (miRs). miRs are endogenous, small non-coding RNAs that facilitate sequence-dependent post-transcriptional gene regulation and coordinately target gene networks of complex biological processes, such as cellular metabolism. However, the role of miRs in mediating osteocyte mitochondrial function has not been explored. This project will test the hypothesis that osteocytic TGFβ signaling regulates mitochondrial function via a miRNA-dependent mechanism to control osteocyte function by focusing on a microRNA cluster, miR-181a/b. Aim 1 will determine the requirement of miR-181a/b for osteocyte function. Aim 2 will determine the extent to which miR-181a/b regulate mitochondrial function in osteocytes. Aim 3 will determine whether the regulation of mitochondrial function by TGFβ is miR-181a/b-dependent. This study will aid our understanding of mechanisms responsible for maintaining homeostatic PLR and potentially aid in the development of new, innovative approaches to treat or prevent bone diseases, including in the craniofacial skeleton, due to bone remodeling defects.

骨中的基质周转通过骨重建发生，并且对于维持骨稳态和骨代谢是必不可少的。 健康骨细胞是嵌入骨基质中的细胞，通过以下两种方式直接调节骨重塑： 控制成骨细胞和破骨细胞的活性，并间接通过骨腔/骨小管重塑 （PLR）。骨细胞在骨重建中调节成骨细胞和破骨细胞活性的能力， 体内平衡是众所周知的，但关于骨细胞在重塑中的直接作用仍存在许多问题， 骨稳态或疾病状态下的PLR。在PLR中，骨细胞直接吸收和存款骨基质 周围的腔隙-小管网络（LCN）。事实上，骨细胞内源性TGFβ信号的缺失， TβRIIocy−/−小鼠导致PLR和骨质缺陷。此外，RNAseq的初步数据显示， TβRIIocy−/−骨显示显著的线粒体功能障碍。然而，潜在的分子机制， TGFβ如何调节骨细胞中的线粒体功能和PLR目前知之甚少。 其他细胞/组织中线粒体功能和代谢的最知名分子调节剂之一 类型是微小RNA（miRs）。miR是内源性的小的非编码RNA，其促进序列依赖性 转录后基因调控和复杂生物过程的协同靶基因网络， 例如细胞代谢。然而，miR在介导骨细胞线粒体功能中的作用还没有被证实。 被探索。 本项目将检验骨细胞TGFβ信号通过调节线粒体功能的假设， 一种通过关注microRNA簇miR-181 a/B来控制骨细胞功能的miRNA依赖性机制。目的1将确定miR-181 a/B对骨细胞功能的需求。目标2将决定 miR-181 a/B调节骨细胞线粒体功能的程度。目标3将决定 TGFβ对线粒体功能的调节是miR-181 a/b依赖性的。这项研究将有助于我们了解 负责维持稳态PLR的机制， 治疗或预防骨疾病的创新方法，包括由于骨 重塑缺陷