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MicroRNA regulation of osteoblast physiology and glucocorticoid signaling

MicroRNA对成骨细胞生理学和糖皮质激素信号传导的调节

基本信息

批准号：
10228365
负责人：
Anne M Delany
金额：
$ 44.46万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
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：
2021-05-14 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10228365
关键词：
Adverse effects Aging Animals Biology CREB1 gene Calvaria Cell Nucleus Cells Corticosterone Critical Pathways Data Energy Metabolism Enzyme-Linked Immunosorbent Assay Female Gene Expression Gene Expression Profiling Genes Glucocorticoid Receptor Glucocorticoids Histology Immunoprecipitation In Vitro Investigation MAP Kinase Gene Mesenchymal Messenger RNA Metabolic Metabolic Diseases MicroRNAs Molecular Molecular Chaperones Mus Osteoblasts Osteocalcin Osteogenesis Osteopenia Pathway interactions Periodicity Peripheral Phenotype Physiology Pituitary-dependent Cushing&apos s disease RNA Receptor Signaling Regulation Role Serum Signal Pathway Signal Transduction Skeleton Syndrome Testing Thick Tissues Transgenic Mice Work bone bone health bone loss circadian cortical bone crosslink design in vivo inhibitor/antagonist knock-down male microCT novel novel strategies osteoblast differentiation p38 Mitogen Activated Protein Kinase prednisolone residence response skeletal substantia spongiosa therapeutic miRNA transcriptome sequencing virtual

项目摘要

Endogenous glucocorticoids are critical for normal bone physiology. However, glucocorticoid excess, due to systemic administration or syndromes such as Cushing’s disease, causes osteopenia and metabolic disorder. Overall, glucocorticoid receptor signaling must be tightly controlled for optimal bone health. We identified microRNA-433 (miR-433) as negative regulator of glucocorticoid signaling in the osteoblast lineage. In vitro, inhibition of miR-433 activity made mesenchymal cells more responsive to glucocorticoids and increased glucocorticoid receptor residence in the nucleus, suggesting that miR-433 may target mechanisms designed to limit the responsiveness of cells to glucocorticoid signaling. In addition to effects on glucocorticoid signaling, miR-433 is a negative regulator of osteoblastic differentiation. miR-433 decreases as osteoblast differentiation progresses, and inhibition of miR-433 activity increases osteoblastic maker gene expression. To better understand the function of miR-433 in bone, we generated transgenic mice expressing a miR-433 competitive inhibitor (tough decoy) in osteoblastic cells. Calvarial bone from the miR-433 decoy mice has increased mRNA for osteocalcin and the direct miR-433 target Runx2. Further, miR-433 decoy mice display increased trabecular and cortical bone thickness due to increased bone formation, although molecular mechanisms remain to be identified. We propose to test the hypothesis that miR-433 targets genes and pathways critical for osteoblastogenesis and for limiting glucocorticoid receptor signaling. In Aim 1, we will comprehensively characterize the skeletal phenotype of both male and female miR-433 decoy mice in maturity and aging. We will also identify miR-433 targets using a non-biased approach, to better understand how miR-433 regulates osteoblast biology. In Aim 2, we will determine the mechanisms by which miR-433 limits glucocorticoid responsiveness at a molecular level, as well as determining the impact of miR- 433 on the response of bone to exogenous glucocorticoids excess. Overall Impact: miR-433 is a novel negative of both glucocorticoid responsiveness and osteoblast differentiation. Glucocorticoid excess is the most common secondary cause of osteopenia, and tissue sensitivity to glucocorticoids is regulated by multiple mechanisms. Understanding the interaction between osteoblastogenesis and glucocorticoid signaling is critical for the design of novel strategies to limit the adverse effects of glucocorticoid excess on the skeleton.

内源性糖皮质激素对正常骨生理至关重要。然而，糖皮质激素过量，应有