Long non-coding RNA <i>Malat1</i> fine-tunes bone homeostasis and repair by orchestrating cellular crosstalk and β-catenin-OPG/Jagged1 pathway.

Abstract

The IncRNA <i>Malat1</i> was initially believed to be dispensable for physiology due to the lack of observable phenotypes in <i>Malat1</i> knockout (KO) mice. However, our study challenges this conclusion. We found that both <i>Malat1</i> KO and conditional KO mice in the osteoblast lineage exhibit significant osteoporosis. Mechanistically, <i>Malat1</i> acts as an intrinsic regulator in osteoblasts to promote osteogenesis. Interestingly, <i>Malat1</i> does not directly affect osteoclastogenesis but inhibits osteoclastogenesis in a non-autonomous manner in vivo via integrating crosstalk between multiple cell types, including osteoblasts, osteoclasts, and chondrocytes. Our findings substantiate the existence of a novel remodeling network in which <i>Malat1</i> serves as a central regulator by binding to β-catenin and functioning through the β-catenin-OPG/Jagged1 pathway in osteoblasts and chondrocytes. In pathological conditions, <i>Malat1</i> significantly promotes bone regeneration in fracture healing. Bone homeostasis and regeneration are crucial to well-being. Our discoveries establish a previous unrecognized paradigm model of <i>Malat1</i> function in the skeletal system, providing novel mechanistic insights into how a lncRNA integrates cellular crosstalk and molecular networks to fine tune tissue homeostasis, remodeling and repair.