Dancr-BRG1 regulates Nfatc1 transcription and Pgc1β- dependent metabolic shifts in osteoclastogenesis

Long non- coding RNA (lncRNA) serves as a vital regulator of bone metabolism, but its role in pathologically overactive osteoclast differentiation remains elusive. Here, we identify lncRNA Dancr (Differentiation Antagonizing Non- protein Coding RNA) as a critical suppressor of osteoclastogenesis and bone resorption, which is down- regulated in response to estrogen deficiency. Global or osteoclast- specific Dancr Knockout mice display significant trabecular bone deterioration and enhanced osteoclast activity, but minimal alteration of bone formation. Moreover, the bone- targeted delivery of Dancr by Adeno- associated viral remarkably attenuates ovariectomy- induced osteopenia in mice. Mechanistically, Dancr establishes a direct interaction with Brahma- related gene 1 to prevent its binding and preserve H3K27me3 enrichment at the nuclear factor of activated T cells 1 and proliferator- activated receptor gamma coactivator 1 - beta promoters, thereby maintaining appropriate expression of osteoclastic genes and metabolic programs during osteoclastogenesis. These results demonstrate that Dancr is a key molecule maintaining proper osteoclast differentiation and bone homeostasis under physiological conditions, and Dancr overexpression constitutes a potential strategy for treating osteoporosis.