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Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to differentiate into osteoblasts or adipocytes, and the shift between osteogenic and adipogenic differentiation determines bone mass. The aim of this study was to identify whether lncRNAs are involved in the differentiation commitment of BMSCs during osteoporosis. Here, we found ORLNC1, a functionally undefined lncRNA that is highly conserved, which exhibited markedly higher expression levels in BMSCs, bone tissue, and the serum of OVX-induced osteoporotic mice than sham-operated counterparts. Notably, a similar higher abundance of lncRNA-ORLNC1 expression was also observed in the bone tissue of osteoporotic patients. The transgenic mice overexpressing lncRNA-ORLNC1 showed a substantial increase in the osteoporosis-associated bone loss and decline in the osteogenesis of BMSCs. The BMSCs pretreated with …