Long non-coding RNA Malat1 is essential for fine-tuning bone homeostasis through orchestrating cellular crosstalk and the β-catenin-OPG/Jagged1 pathway.

The annotation of lncRNAs is transitioning from original sequence recognition and functional screening in vitro to comprehensive functional and mechanistic studies in vivo, anchored in genetic evidence. This shift is crucial for definitively understanding the roles of lncRNAs, particularly in vivo contexts such as development, metabolism, homeostasis, and tissue remodeling. Contrary to the initial belief that Malat1 (metastasis associated lung adenocarcinoma transcript 1) is dispensable for mouse physiology due to the lack of observable phenotypes in Malat1 knockout (KO) mice, our study challenges and overturns this previous conclusion. We examined both Malat1 KO and conditional KO mice in the osteoblast lineage, and found that these mice exhibit significant osteoporosis. Our data further demonstrate that Malat1 emerges as a novel regulator impacting multiple cell types, including osteoblasts, osteoclasts, and chondrocytes, in bone homeostasis and remodeling. Mechanistically, Malat1 plays a dual role, promoting osteoblastic bone formation while suppressing osteoclastic bone resorption. Our findings substantiate the existence of a novel remodeling network in which Malat1 serves as a central regulator by binding to β-catenin. It orchestrates the β-catenin pathway, autonomously enhancing osteogenesis in osteoblasts while non-autonomously suppressing osteoclastogenesis through the β-catenin-OPG/Jagged1 axis in osteoblasts and chondrocytes. Bone homeostasis is crucial to well-being but often overlooked. These discoveries establish the first paradigm model of Malat1 function in the skeletal system, providing novel mechanistic insights into how a lncRNA integrates cellular crosstalk and molecular networks to fine tune tissue homeostasis and remodeling.