Extracellular Vesicle-Encapsulated miR-29b-3p Released From Bone Marrow-Derived Mesenchymal Stem Cells Underpins Osteogenic Differentiation

Abstract

Objective: Mesenchymal stem cells (MSCs) confer therapeutic benefits in various pathologies and cancers by releasing extracellular vesicles (EVs) loaded with bioactive compounds. Herein, we identified bone marrow MSC (BMSC)-derived EVs harboring microRNA (miR)-29b-3p to regulate osteogenic differentiation through effects on the suppressor of cytokine signaling 1 (SOCS1)/nuclear factor (NF)-κB pathway via targeting of lysine demethylase 5A (KDM5A) in osteoporosis. Methods: We quantified the miR-29b-3p in BMSC-derived EVs from bone marrow specimens of osteoporotic patients and non-osteoporotic patients during total hip arthroplasty (THA). miR-29b-3p targeting KDM5A was confirmed by promoter luciferase assay, and enrichment of KDM5A in the promoter region of SOCS1 was analyzed by chromatin immunoprecipitation (ChIP). The expression and translocation of NF-κB to the nucleus were detected by western blot analysis and immunofluorescence staining, respectively. An ovariectomized (OVX) osteoporosis mouse model was established to further confirm the in vitro findings. Results: BMSC-derived EVs of osteoporotic patients exhibited downregulated miR-29b-3p. EV-encapsulated miR-29b-3p from BMSCs potentiated osteogenic differentiation by specifically inhibiting KDM5A. KDM5A inhibited osteogenic differentiation by the regulation of H3K4me3 and H3K27ac of SOCS1. SOCS1 potentiated osteogenic differentiation by inhibiting NF-κB pathway. Conclusion: EV-encapsulated miR-29b-3p derived from BMSCs potentiated osteogenic differentiation through blockade of the SOCS1/NF-κB pathway by inhibition of KDM5A.