Long Noncoding RNA Malat1 Protects Against Osteoporosis and Bone Metastasis

Authors

Yang Zhao
Jingyuan Ning
Hongqi Teng
Yalan Deng
Marisela Sheldon
Lei Shi
Consuelo Martinez
Jie Zhang
Annie Tian
Yutong Sun
Shinichi Nakagawa
Fan Yao
Hai Wang
Li Ma

Publication Date

3-16-2024

Journal

Nature Communications

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.

Keywords

Animals, Humans, Mice, Macrophages, Osteoclasts, Osteogenesis, Osteoporosis, RNA, Long Noncoding

Comments

This article has been corrected. See Nat Commun. 2024 June 10; 15: 4937.

Supplementary Materials

Data Availability Statement

PMID: 38493144