期刊
CURRENT STEM CELL RESEARCH & THERAPY
卷 18, 期 1, 页码 115-126出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1574888X17666220426120850
关键词
Osteoporosis Treatment; Antagomir-483-5p; BMSC Osteoblastic Differentiation; MAPK1; Smad5; Targeted Drug Delivery
This study demonstrates that miR-483-5p inhibits the osteogenic differentiation of BMSCs, and selectively delivering antagomir-483-5p to BMSCs using nanoparticles can promote osteoblastic differentiation and prevent osteoporosis. The research also identified MAPK1 and Smad5 as direct targets of miR-483-5p in regulating BMSC osteoblastic differentiation and osteoporosis.
Background: 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. Methods: Real-time PCR assays were used to analyze miR-483-5p, ALP and Bglap levels in BMSCs of ovariectomized and aged osteoporotic mice. Immunoglobulin G and poloxamer-188 encapsulated the functional small molecules, and a BMSC-targeting aptamer was employed to confirm the direction of the nanoparticles to selectively and efficiently deliver antagomir-483-5p to BMSCs in vivo. 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 in vivo. Results: miR-483-5p levels were increased in BMSCs of ovariectomized and aged osteoporotic mice. Inhibiting 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. Conclusions: The important therapeutic role of FAM-BMSC-aptamer-nanoparticles carrying antagomir-483-5p in osteoporosis was established in our study. These nanoparticles are a novel candidate for the clinical prevention and treatment of osteoporosis. The optimized, targeted drug delivery platform for small molecules will provide new ideas for treating clinical diseases.
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