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The characteristics of mesenchymal stromal cells (MSCs) which derived from multiple myeloma (MM) patients are typically impaired in osteogenic differentiation. However, the underlying molecular mechanisms need to be further investigated. lncRNAs are emerging as critical regulation molecules in oncogenic pathways. In this study, we identified that bioactive lncRNA HOXC‐AS3, which is transcribed in opposite to HOXC10, was presented in MSCs derived from bone marrow (BM) of MM patients (MM‐MSCs). HOXC‐AS3 was able to interact with HOXC10 at the overlapping parts and this interaction increased HOXC10 stability, then promoted its expression, conferring osteogenesis repression to MM‐MSCs. In mouse models, intravenously administered siHOXC‐AS3 was proven to be effective in prevention of bone loss, sustained by both anticatabolic activities and bone‐forming. These data showed that lncHOXC‐AS3 was required for osteogenesis in BM‐MSCs by enhancing HOXC10 expression. Our finding thus unveils a novel insight for the potential clinical significance of lncRNA HOXC‐AS3 as a therapeutic target for bone disease in MM. S tem  C ells   2019;37:247–256

HOXC10 Regulates Osteogenesis of Mesenchymal Stromal Cells Through Interaction with Its Natural Antisense Transcript lncHOXC‐AS3