Nanoparticles Targeting Delivery Antagomir-483 -5p to Bone Marrow Mesenchymal Stem Cells Treat Osteoporosis by Increasing Bone Formation.

Promoting bone marrow mesenchymal stem cell (BMSC) osteoblastic differentiation is a promising therapeutic strategy for osteoporosis (OP). The present study demonstrates that miR-483-5p inhibits the osteogenic differentiation of BMSCs. Therefore, selectively delivering the nanoparticles carrying antagomir-483-5p (miR-483-5p inhibitor) to BMSCs is expected to become an effective treatment drug for OP.Real-time PCR assays were used to analyze miR-483-5p, ALP and Bglap levels in BMSCs of ovariectomized and aged osteoporotic mice. To selectively and efficiently delivering antagomir-483-5p to BMSCs in vivo, immunoglobulin G and poloxamer-188 were used to encapsulate the functional small molecules, and BMSC-targeting aptamer was employed to confirm the direction of the nanoparticles. Luciferase assays were used to determine the target genes of miR-483-5p. Western blot assays and immunohistochemistry staining were used to detect the targets in vitro and vivo.miR-483-5p levels were increased in BMSCs of ovariectomized and aged osteoporotic mice. Inhibition of miR-483-5p levels in BMSCs by antagomir-483-5p in vitro promoted the expression of bone formation markers, such as ALP and Bglap. The FAM-BMSC-aptamer-nanoparticles carrying antagomir-483-5p were taken up by BMSCs, resulting in stimulation of BMSC osteoblastic differentiation in vitro and osteoporosis prevention in vivo. Furthermore, our research demonstrated that mitogen-activated protein kinase 1 (MAPK1) and SMAD family member 5 (Smad5) were direct targets of miR-483-5p in regulating BMSC osteoblastic differentiation and osteoporosis pathological processes.The important therapeutic role of FAM-BMSC-aptamer-nanoparticles carrying antagomir-483-5p in osteoporosis was established in our study. These nanoparticles are novel candidate for the clinical prevention and treatment of osteoporosis. The optimized targeted drug delivery platform for small molecules will provide new ideas for the treatment of clinical diseases.