BMP9 promotes osteogenic differentiation of BMSCs via the lncRNA SNHG3/miR-619-5p axis in a breast cancer bone metastatic microenvironment.

Bone morphogenetic protein 9 (BMP9), the most potent osteogenic member of the bone morphogenetic protein (BMP) family, is well-documented to potently induce the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). However, its role in regulating osteogenesis in the breast cancer (BC) bone microenvironment remains poorly understood. By constructing BMP9-overexpressing MDA-MB-231 cell lines through adenovirus-mediated exogenous overexpression of BMP9 or adding BMP9 recombinant protein to the culture system, as well as establishing a nude mouse humerus injection model, we explored the effect and mechanism of BMP9 in the BC bone metastasis microenvironment. We also clarified the relevant molecular mechanisms using techniques such as exosome miRNA sequencing, qRT-PCR, Western blot, histochemical staining, immunofluorescence staining, and bioinformatics. Through a series of experiments and the nude mouse humerus injection model, we verified that BMP9 promotes osteogenic differentiation of BMSCs and collagen fiber regeneration in nude mice by downregulating the level of lncRNA SNHG3 in BC. From a mechanistic perspective, exosome miRNA sequencing and bioinformatics analysis revealed that downregulation of lncRNA SNHG3 can facilitate the osteogenic differentiation of BMSCs, while suppressing the proliferation, migration, and invasion of MDA-MB-231 cells by delivering exosomal miR-619-5p. This study reveals that BMP9/lncRNA SNHG3/miR-619-5p axis promotes osteogenic differentiation of BMSCs in breast cancer, suggesting that BMP9 and miR-619-5p may become new strategies for treating BC bone metastasis, and lncRNA SNHG3 can act as a potential therapeutic target.