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：
10432113
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/10432113
关键词：
Adult Albers-Schonberg disease Animal Model Biology Biomechanics Bone Diseases 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 beta catenin bone bone cell bone mass bone repair 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.

调节骨稳态和通过长不编码RNA malat1进行重塑骨稳态通过破骨细胞介导的骨头之间的恒定和动态重塑来维持分辨率和成骨细胞/骨细胞介导的骨形成。骨骼重塑过程的平衡，然而，在病理状况（例如骨质疏松症和类风湿关节炎）中，通常会受到干扰。调节骨骼重塑的机制尚不完全了解。最近的基因组研究已经揭示功能性长的非编码RNA（LNCRNA）和靶向LNCRNA提供了令人兴奋的新的人类疾病的诊断和治疗机会。参与骨骼重塑的LNCRNA，但是，被低估了。 Malat1是最保守和最丰富的核LNCRNA之一。这 Malat1的功能在骨稳态和重塑中未知。我们第一次透露 Malat1 KO小鼠暴露了明显的骨质疏松骨表型，其特征在于破骨碎屑骨骼分辨率，但在体内减少了成骨细胞骨形成。那就是malat1删除未耦合的成骨细胞和破骨细胞之间的正常骨重塑。 Malat1在成骨细胞以促进成骨细胞分化，但抑制了非自治的破骨细胞生成体内的方式。此外，Malat1调节成骨细胞和破骨细胞之间的串扰。从机械上讲，MALAT1缺乏症显着降低了β-catenin的核定位成骨细胞生成。富含成骨细胞信号，骨化和Wnt/β-的基因在MALAT1 KO成骨细胞中，链氨酸蛋白酶途径被选择性地抑制。这些发现识别lncrna malat1是一种新型的骨重塑调节剂，影响骨骼稳态。控制骨形成和分辨率。在此应用中，我们将采用强大的遗传方法来研究功能重要性成骨细胞谱系中Malat1的及其调节成骨和成骨的机制成骨细胞 - 稳态。具体而言，我们将1）解剖和定义malat1的功能使用遗传方法在体内分化的各个阶段的成骨细胞谱系； 2）调查 MALAT1调节成骨和成骨细胞crosstalk的机制。成功的拟议研究的完成将在骨场中引入功能性lncrnas，产生新的见解进入调节骨体内稳态和重塑的LNCRNA介导的机制，并将提供开发基于LNCRNA的新型或替代治疗方法的理性框架疾病。