Long noncoding RNA Malat1 inhibits Tead3-Nfatc1–mediated osteoclastogenesis to suppress 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 new roles of MALAT1 in physiological and pathological processes, we found that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Notably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis, 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. Altogether, these findings identify Malat1 as a lncRNA that suppresses osteoporosis and bone metastasis.

LncRNA-mediated cartilage homeostasis in osteoarthritis: a narrative review

“…LncRNAs not only affect transcriptional regulation, chromatin remodeling, and the regulation of gene expression in cells but also regulate cell proliferation, differentiation, the inflammatory response, extracellular matrix metabolism, and autophagy in OA (14). Several lncRNAs associated with the inflammatory response, such as MALAT1 (15), H19 (16) and NEAT1 (17), can be involved in the expression of inflammatory factors and regulation of the inflammatory response by interacting with transcription factors or RNA regulatory factors. Several lncRNAs, such as ANCR, lncRNA-HOTAIR and lncRNA-XIST, are also potentially involved in the metabolism and repair of bone and joint tissues (18)(19)(20).…”