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Regulation of bone homeostasis and remodeling by long noncoding RNA Malat1

长链非编码 RNA Malat1 调节骨稳态和重塑

基本信息

批准号：
10295912
负责人：
Baohong Zhao
金额：
$ 46.4万
依托单位：
HOSPITAL FOR SPECIAL SURGERY
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：
2021-07-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10295912
关键词：
Adult Albers-Schonberg disease Animal Model Biology Biomechanics Bone Diseases Bone Regeneration Bone Resorption Bone remodeling Cardiovascular Diseases Categories Cell Differentiation process Cell physiology Cells Complex Coupling Development Disease Epigenetic Process Equilibrium Exhibits Future Gene Expression Regulation Genes Genetic Diseases Genetic Transcription Genomics Goals Homeostasis In Vitro Innate Bone Remodeling Knock-out Knockout Mice Life MALAT1 gene Malignant Neoplasms Mediating Mesenchymal Stem Cells Molecular Mus Nuclear Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Osteosclerosis Pathologic Pathway interactions Phenotype Physiologic Ossification Process RNA Splicing Regulation Reporting Rheumatoid Arthritis Signal Transduction Skeleton Techniques Testing Therapeutic Time Transcript Transcriptional Regulation Transgenic Mice Treatment Efficacy Untranslated RNA base beta catenin bone bone cell bone mass cell type conditional knockout epigenetic regulation genetic approach human disease in vivo insight mRNA Precursor novel novel diagnostics novel therapeutic intervention novel therapeutics osteoblast differentiation osteoclastogenesis osteogenic osteoporotic bone prevent reconstitution scaffold skeletal skeletal disorder transcriptome sequencing

项目摘要

Regulation of bone homeostasis and remodeling by long noncoding RNA Malat1 Bone homeostasis is maintained by constant and dynamic remodeling between osteoclast-mediated bone resorption and osteoblast/osteocyte-mediated bone formation. The balance of bone remodeling process, however, is often disrupted in pathological conditions, such as in osteoporosis and rheumatoid arthritis. The mechanisms that regulate bone remodeling are not fully understood. Recent genomic studies have unveiled functional long noncoding RNAs (lncRNAs), and targeting lncRNAs provided exciting new diagnostic and therapeutic opportunities for human diseases. The lncRNAs involved in bone remodeling, however, are underappreciated. Malat1 is one of the most conserved and abundant nuclear lncRNAs. The function of Malat1 is unknown in bone homeostasis and remodeling. We revealed, for the first time, that Malat1 KO mice exhibit significant osteoporotic bone phenotype characterized with enhanced osteoclastic bone resorption, but reduced osteoblastic bone formation in vivo. Thus, Malat1 deletion uncoupled the normal bone remodeling between osteoblasts and osteoclasts. Malat1 acts cell-autonomously in osteoblasts to promote osteoblast differentiation, but suppresses osteoclastogenesis in a non-autonomous manner in vivo. Moreover, Malat1 modulates crosstalk between osteoblasts and osteoclasts. Mechanistically, Malat1 deficiency significantly reduced nuclear localization of β-catenin during osteoblastogenesis. The genes enriched in pathways of osteoblast signaling, ossification, and Wnt/β- catenin pathway were selectively and significantly suppressed in Malat1 KO osteoblasts. These findings identify lncRNA Malat1 as a novel bone remodeling regulator that impacts skeletal homeostasis by controlling both bone formation and resorption. In this application, we will apply robust genetic approaches to investigate the functional importance of Malat1 in osteoblast lineage and the mechanisms by which Malat1 regulates osteogenesis and osteoblast-osteoclast crosstalk. Specifically, we will 1) dissect and define the function of Malat1 in osteoblast lineage at various stages of differentiation in vivo using genetic approaches; 2) investigate the mechanisms by which Malat1 regulates osteogenesis and osteoblast-osteoclast crosstalk. Successful completion of the proposed studies will introduce functional lncRNAs into bone field, yield novel insights into lncRNA-mediated mechanisms that regulate bone homeostasis and remodeling, and will provide a rational framework for developing lncRNA-based new or alternative therapeutic approaches for skeletal diseases.

长链非编码 RNA Malat1 调节骨稳态和重塑骨稳态通过破骨细胞介导的骨之间持续和动态的重塑来维持吸收和成骨细胞/骨细胞介导的骨形成。骨重建过程的平衡，然而，在骨质疏松症和类风湿性关节炎等病理情况下，它经常被破坏。调节骨重塑的机制尚不完全清楚。最近的基因组研究表明揭开了功能性长非编码 RNA (lncRNA) 的面纱，靶向 lncRNA 提供了令人兴奋的新功能人类疾病的诊断和治疗机会。参与骨重塑的lncRNA，然而，却被低估了。 Malat1 是最保守、最丰富的核 lncRNA 之一。这 Malat1 在骨稳态和重塑中的功能尚不清楚。我们首次透露， Malat1 KO 小鼠表现出明显的骨质疏松骨表型，其特征是破骨细胞增强骨吸收，但减少体内成骨细胞骨形成。因此，Malat1 缺失使成骨细胞和破骨细胞之间的正常骨重塑。 Malat1 的细胞自主作用成骨细胞促进成骨细胞分化，但抑制非自主性破骨细胞生成体内方式。此外，Malat1 调节成骨细胞和破骨细胞之间的串扰。从机制上讲，Malat1 缺陷显着降低了 β-catenin 的核定位。成骨细胞发生。富含成骨细胞信号传导、骨化和 Wnt/β- 通路的基因 Malat1 KO 成骨细胞中连环蛋白途径被选择性且显着抑制。这些发现确定 lncRNA Malat1 是一种新型骨重塑调节因子，通过以下方式影响骨骼稳态控制骨形成和骨吸收。在此应用中，我们将应用稳健的遗传方法来研究功能重要性 Malat1 在成骨细胞谱系中的作用以及 Malat1 调节成骨和成骨的机制成骨细胞-破骨细胞串扰。具体来说，我们将 1) 剖析并定义 Malat1 的函数使用遗传方法在体内不同分化阶段的成骨细胞谱系； 2）调查 Malat1 调节成骨和成骨细胞-破骨细胞串扰的机制。成功的拟议研究的完成将把功能性lncRNA引入骨领域，产生新的见解进入lncRNA介导的调节骨稳态和重塑的机制，并将提供开发基于 lncRNA 的新的或替代的骨骼治疗方法的合理框架疾病。