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.