Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis

Abstract

MALAT1, one of the few highly conserved nuclear long noncoding RNAs (lncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover the fundamental roles of MALAT1 in physiological and pathological processes, we find that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Remarkably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis of melanoma and mammary tumor cells, which can be rescued by genetic add-back of Malat1. Mechanistically, Malat1 binds to Tead3 protein, a macrophage-osteoclast–specific Tead family member, blocking Tead3 from binding and activating Nfatc1, a master regulator of osteoclastogenesis, which results in the inhibition of Nfatc1-mediated gene transcription and osteoclast differentiation. Notably, single-cell transcriptome analysis of clinical bone samples reveals that reduced MALAT1 expression in pre-osteoclasts and osteoclasts is associated with osteoporosis and metastatic bone lesions. Altogether, these findings identify Malat1 as a lncRNA that protects against osteoporosis and bone metastasis.

Epimedium‐Curculigo herb pair enhances bone repair with infected bone defects and regulates osteoblasts through LncRNA MALAT1/miR‐34a‐5p/SMAD2 axis

“…Furthermore, research indicates that the expression of LncRNA MALAT1 is decreased during the process of osteoclast differentiation, leading to bone resorption, ultimately contributing to low bone mineral density and the development of osteoporosis. 49 It is hypothesized that LncRNA MALAT1 plays a significant role in bone repair by promoting osteoblast function and inhibiting osteoclast activity, thereby serving as a potential therapeutic target for the prevention and treatment of osteoporosis and bone defects. Finally, we validated the efficacy of ECP‐CS on osteoblasts.…”