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Current Stem Cell Research & Therapy

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ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

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Research Article

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

Author(s): Yue Zhou, Hao Jia, Aihua Hu, Rangru Liu, Xiangzhou Zeng and Hua Wang*

Volume 18, Issue 1, 2023

Published on: 21 July, 2022

Page: [115 - 126] Pages: 12

DOI: 10.2174/1574888X17666220426120850

Price: $65

Abstract

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.

Keywords: Osteoporosis treatment, Antagomir-483-5p, BMSC osteoblastic differentiation, MAPK1, Smad5, Targeted drug delivery.

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[1]
Prince RL, Lewis JR, Lim WH, et al. Adding lateral spine imaging for vertebral fractures to densitometric screening: Improving ascertainment of patients at high risk of incident osteoporotic fractures. J Bone Miner Res 2019; 34(2): 282-9.
[http://dx.doi.org/10.1002/jbmr.3595] [PMID: 30395687]
[2]
Zhou T, Yang Y, Chen Q, Xie L. Glutamine metabolism is essential for stemness of bone marrow mesenchymal stem cells and bone homeostasis. Stem Cells Int 2019; 2019: 8928934.
[http://dx.doi.org/10.1155/2019/8928934] [PMID: 31611919]
[3]
Balani DH, Ono N, Kronenberg HM. Parathyroid hormone regulates fates of murine osteoblast precursors in vivo. J Clin Invest 2017; 127(9): 3327-38.
[http://dx.doi.org/10.1172/JCI91699] [PMID: 28758904]
[4]
Fan Y, Hanai JI, Le PT, et al. Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab 2017; 25(3): 661-72.
[http://dx.doi.org/10.1016/j.cmet.2017.01.001] [PMID: 28162969]
[5]
Kraenzlin ME, Meier C. Parathyroid hormone analogues in the treatment of osteoporosis. Nat Rev Endocrinol 2011; 7(11): 647-56.
[http://dx.doi.org/10.1038/nrendo.2011.108] [PMID: 21750510]
[6]
Yang A, Yu C, Lu Q, Li H, Li Z, He C. Mechanism of action of icariin in bone marrow mesenchymal stem cells. Stem Cells Int 2019; 2019: 5747298.
[http://dx.doi.org/10.1155/2019/5747298] [PMID: 31089330]
[7]
Yang TL, Shen H, Liu A, et al. A road map for understanding molecular and genetic determinants of osteoporosis. Nat Rev Endocrinol 2020; 16(2): 91-103.
[http://dx.doi.org/10.1038/s41574-019-0282-7] [PMID: 31792439]
[8]
Kokabu S, Lowery JW, Jimi E. Cell fate and differentiation of bone marrow mesenchymal stem cells. Stem Cells Int 2016; 2016: 3753581.
[http://dx.doi.org/10.1155/2016/3753581] [PMID: 27298623]
[9]
Yang A, Yu C, You F, He C, Li Z. Mechanisms of Zuogui Pill in Treating Osteoporosis: Perspective from Bone Marrow Mesenchymal Stem Cells. Evid Based Complement Alternat Med 2018; 2018: 3717391.
[http://dx.doi.org/10.1155/2018/3717391] [PMID: 30327678]
[10]
Wang C, Meng H, Wang X, Zhao C, Peng J, Wang Y. Differentiation of bone marrow mesenchymal stem cells in osteoblasts and adipocytes and its role in treatment of osteoporosis. Med Sci Monit 2016; 22: 226-33.
[http://dx.doi.org/10.12659/MSM.897044] [PMID: 26795027]
[11]
Jin Z, Chen J, Shu B, Xiao Y, Tang D. Bone mesenchymal stem cell therapy for ovariectomized osteoporotic rats: A systematic review and meta-analysis. BMC Musculoskelet Disord 2019; 20(1): 556.
[http://dx.doi.org/10.1186/s12891-019-2851-2] [PMID: 31747888]
[12]
Li CJ, Cheng P, Liang MK, et al. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J Clin Invest 2015; 125(4): 1509-22.
[http://dx.doi.org/10.1172/JCI77716] [PMID: 25751060]
[13]
Zhang L, Tang Y, Zhu X, et al. Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice. J Bone Miner Res 2017; 32(12): 2466-75.
[http://dx.doi.org/10.1002/jbmr.3230] [PMID: 28846804]
[14]
Hu B, Li Y, Wang M, et al. Functional reconstruction of critical-sized load-bearing bone defects using a Sclerostin-targeting miR-210-3p-based construct to enhance osteogenic activity. Acta Biomater 2018; 76: 275-82.
[http://dx.doi.org/10.1016/j.actbio.2018.06.017] [PMID: 29898419]
[15]
Lin Z, He H, Wang M, Liang J. MicroRNA-130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate. Cell Prolif 2019; 52(6): e12688.
[http://dx.doi.org/10.1111/cpr.12688] [PMID: 31557368]
[16]
Li Y, Yang F, Gao M, et al. miR-149-3p regulates the switch between adipogenic and osteogenic differentiation of BMSCs by targeting FTO. Mol Ther Nucleic Acids 2019; 17: 590-600.
[http://dx.doi.org/10.1016/j.omtn.2019.06.023] [PMID: 31382190]
[17]
Long H, Zhu Y, Lin Z, et al. miR-381 modulates human bone mesenchymal stromal cells (BMSCs) osteogenesis via suppressing Wnt signaling pathway during atrophic nonunion development. Cell Death Dis 2019; 10(7): 470.
[http://dx.doi.org/10.1038/s41419-019-1693-z] [PMID: 31209205]
[18]
Hu Z, Zhang L, Wang H, et al. Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice. Stem Cell Res Ther 2020; 11(1): 58.
[http://dx.doi.org/10.1186/s13287-020-1581-6] [PMID: 32054528]
[19]
Zuntini M, Salvatore M, Pedrini E, et al. MicroRNA profiling of multiple osteochondromas: Identification of disease-specific and normal cartilage signatures. Clin Genet 2010; 78(6): 507-16.
[http://dx.doi.org/10.1111/j.1399-0004.2010.01490.x] [PMID: 20662852]
[20]
Wang H, Zhang H, Sun Q, et al. Intra-articular delivery of antago-miR-483-5p inhibits osteoarthritis by modulating matrilin 3 and tissue inhibitor of metalloproteinase 2. Mol Ther 2017; 25(3): 715-27.
[http://dx.doi.org/10.1016/j.ymthe.2016.12.020] [PMID: 28139355]
[21]
Wang H, Zhang H, Sun Q, et al. Chondrocyte mTORC1 activation stimulates miR-483-5p via HDAC4 in osteoarthritis progression. J Cell Physiol 2019; 234(3): 2730-40.
[http://dx.doi.org/10.1002/jcp.27088] [PMID: 30145794]
[22]
Chen K, He H, Xie Y, et al. miR-125a-3p and miR-483-5p promote adipogenesis via suppressing the RhoA/ROCK1/ERK1/2 pathway in multiple symmetric lipomatosis. Sci Rep 2015; 5(1): 11909.
[http://dx.doi.org/10.1038/srep11909] [PMID: 26148871]
[23]
De-Ugarte L, Yoskovitz G, Balcells S, et al. MiRNA profiling of whole trabecular bone: Identification of osteoporosis-related changes in MiRNAs in human hip bones. BMC Med Genomics 2015; 8(1): 75.
[http://dx.doi.org/10.1186/s12920-015-0149-2] [PMID: 26555194]
[24]
Li K, Chen S, Cai P, et al. MiRNA-483-5p is involved in the pathogenesis of osteoporosis by promoting osteoclast differentiation. Mol Cell Probes 2020; 49: 101479.
[http://dx.doi.org/10.1016/j.mcp.2019.101479] [PMID: 31706013]
[25]
Perepelyuk M, Maher C, Lakshmikuttyamma A, Shoyele SA. Aptamer-hybrid nanoparticle bioconjugate efficiently delivers miRNA-29b to non-small-cell lung cancer cells and inhibits growth by downregulating essential oncoproteins. Int J Nanomedicine 2016; 11: 3533-44.
[http://dx.doi.org/10.2147/IJN.S110488] [PMID: 27555773]
[26]
Sacko K, Thangavel K, Shoyele SA. Codelivery of Genistein and miRNA-29b to A549 Cells Using Aptamer-Hybrid Nanoparticle Bioconjugates. Nanomaterials (Basel) 2019; 9(7): E1052.
[http://dx.doi.org/10.3390/nano9071052] [PMID: 31340494]
[27]
Luo ZW, Li FX, Liu YW, et al. Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration. Nanoscale 2019; 11(43): 20884-92.
[http://dx.doi.org/10.1039/C9NR02791B] [PMID: 31660556]
[28]
Wang H, Zhang H, Fan K, et al. Frugoside delays osteoarthritis progression via inhibiting miR-155-modulated synovial macrophage M1 polarization. Rheumatology (Oxford) 2021; 60(10): 4899-909.
[http://dx.doi.org/10.1093/rheumatology/keab018] [PMID: 33493345]
[29]
Chanpaisaeng K, Reyes Fernandez PC, Fleet JC. Dietary calcium intake and genetics have site-specific effects on peak trabecular bone mass and microarchitecture in male mice. Bone 2019; 125: 46-53.
[http://dx.doi.org/10.1016/j.bone.2019.05.011] [PMID: 31078711]
[30]
Arnold EL, Clement J, Rogers KD, Garcia-Castro F, Greenwood C. The use of μCT and fractal dimension for fracture prediction in osteoporotic individuals. J Mech Behav Biomed Mater 2020; 103: 103585.
[http://dx.doi.org/10.1016/j.jmbbm.2019.103585] [PMID: 32090913]
[31]
Dim N, Perepelyuk M, Gomes O, et al. Novel targeted siRNA-loaded hybrid nanoparticles: Preparation, characterization and in vitro evaluation. J Nanobiotechnology 2015; 13(1): 61.
[http://dx.doi.org/10.1186/s12951-015-0124-2] [PMID: 26410728]
[32]
Lakshmikuttyamma A, Sun Y, Lu B, Undieh AS, Shoyele SA. Stable and efficient transfection of siRNA for mutated KRAS silencing using novel hybrid nanoparticles. Mol Pharm 2014; 11(12): 4415-24.
[http://dx.doi.org/10.1021/mp500525p] [PMID: 25340957]
[33]
Srinivasan AR, Shoyele SA. Self-associated submicron IgG1 particles for pulmonary delivery: Effects of non-ionic surfactants on size, shape, stability, and aerosol performance. AAPS PharmSciTech 2013; 14(1): 200-10.
[http://dx.doi.org/10.1208/s12249-012-9913-1] [PMID: 23255200]
[34]
He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 2010; 31(13): 3657-66.
[http://dx.doi.org/10.1016/j.biomaterials.2010.01.065] [PMID: 20138662]
[35]
He F, Ni N, Zeng Z, et al. FAMSi: A synthetic biology approach to the fast assembly of multiplex siRNAs for silencing gene expression in mammalian cells. Mol Ther Nucleic Acids 2020; 22: 885-99.
[http://dx.doi.org/10.1016/j.omtn.2020.10.007] [PMID: 33230483]
[36]
Lu N, Malemud CJ. Extracellular signal-regulated kinase: A regulator of cell growth, inflammation, chondrocyte and bone cell receptor-mediated gene expression. Int J Mol Sci 2019; 20(15): E3792.
[http://dx.doi.org/10.3390/ijms20153792] [PMID: 31382554]
[37]
Wang J, Wang M, Chen F, et al. Nano-hydroxyapatite coating promotes porous calcium phosphate ceramic-induced osteogenesis via BMP/Smad signaling pathway. Int J Nanomedicine 2019; 14: 7987-8000.
[http://dx.doi.org/10.2147/IJN.S216182] [PMID: 31632013]

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