Regulation of bone homeostasis and remodeling by long noncoding RNA Malat1

长非编码RNA MALAT1对骨稳态和骨重建的调控 破骨细胞介导骨之间的恒定和动态重塑维持骨内稳态 骨吸收与成骨细胞/骨细胞介导骨形成。骨重建过程的平衡， 然而，在病理条件下，例如在骨质疏松症和类风湿性关节炎中，它经常被破坏。 调控骨重塑的机制还不完全清楚。最近的基因组研究已经 揭示了功能性长非编码RNA(LncRNAs)，并针对lncRNAs提供了令人兴奋的新 人类疾病的诊断和治疗机会。参与骨骼重塑的lncRNA， 然而，他们被低估了。MALAT1是最保守、含量最丰富的核转录因子之一。这个 MALAT1在骨内稳态和骨重建中的作用尚不清楚。我们第一次透露， MALAT1 KO小鼠表现出明显的骨质疏松表型，其特征是破骨细胞增强 骨吸收，但体内成骨细胞骨形成减少。因此，MALAT1删除解偶联 成骨细胞和破骨细胞之间的正常骨重建。MALAT1在细胞内的自主作用 成骨细胞促进成骨细胞分化，但抑制破骨细胞生成的非自主性 在活体内的方式。此外，MALAT1还调节成骨细胞和破骨细胞之间的串扰。 在机制上，MALAT1缺乏显著降低了β-连环蛋白的核定位 成骨细胞的形成。富含成骨细胞信号转导、成骨和Wnt/β途径的基因- 在MALAT1KO成骨细胞中，连接素途径被选择性地显著抑制。这些发现 鉴定lncRNA MALAT1是一种新的骨重建调节因子，通过以下方式影响骨骼动态平衡 控制骨形成和吸收。 在这项应用中，我们将应用稳健的遗传学方法来研究功能重要性 MALAT1在成骨细胞系中的表达及其调控成骨和骨形成的机制 成骨细胞-破骨细胞串扰。具体地说，我们将1)剖析和定义MALAT1在 利用遗传学方法在体内不同分化阶段的成骨细胞谱系；2)研究 MALAT1调节成骨和成骨细胞-破骨细胞串扰的机制。成功 拟议研究的完成将把功能性lncRNAs引入骨骼领域，产生新的见解 转化为lncRNA介导的调节骨骼稳态和重塑的机制，并将提供一种 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。

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.