Research progress of exosomes in treatment of osteoporosis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

DUAN Keyou ^1,2 ,  GUAN Jianzhong ^1,2

1. Department of Orthopaedics, the First Affiliated Hospital of Bengbu Medical College, Bengbu Anhui, 233000, P.R.China;
2. Key Laboratory of Anhui Province for Tissue Transplantation, Bengbu Anhui, 233000, P.R.China;

Corresponding author：

GUAN Jianzhong, Email: jzguan2002@163.com

Keywords：

Exosome; osteoporosis; bone remodeling; bone marrow mesenchymal stem cells; osteoblasts; osteoclasts; osteocytes; endothelial cells

DOI：

10.7507/1002-1892.202105106

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the research progress of exosomes (EXOs) derived from different cells in the treatment of osteoporosis (OP). Methods Recent relevant literature about EXOs for OP therapy was extensively reviewed. And the related mechanism and clinical application prospect of EXOs derived from different cells in OP therapy were summarized and analyzed. Results EXOs derived from various cells, including bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, osteocytes, and endothelial cells, et al, can participate in many links in the process of bone remodeling, and their mechanisms involve the regulation of proliferation and differentiation of bone-related cells, the promotion of vascular regeneration and immune regulation, and the suppression of inflammatory reactions. A variety of bioactive substances contained in EXOs are the basis of regulating the process of bone remodeling, and the combination of genetic engineering technology and EXOs-based drug delivery can further improve the therapeutic effect of OP. Conclusion EXOs derived from different cells have great therapeutic effects on OP, and have the advantages of low immunogenicity, high stability, strong targeting ability, and easy storage. EXOs has broad clinical application prospects and is expected to become a new strategy for OP treatment.

Citation： DUAN Keyou, GUAN Jianzhong. Research progress of exosomes in treatment of osteoporosis. Chinese Journal of Reparative and Reconstructive Surgery, 2021, 35(12): 1642-1649. doi: 10.7507/1002-1892.202105106 Copy

1.	Johnston CB, Dagar M. Osteoporosis in older adults. Med Clin North Am, 2020, 104(5): 873-884.
2.	Tsai JN, Lee H, David NL, et al. Combination denosumab and high dose teriparatide for postmenopausal osteoporosis (DATA-HD): a randomised, controlled phase 4 trial. Lancet Diabetes Endocrinol, 2019, 7(10): 767-775.
3.	Aghebati-Maleki L, Dolati S, Zandi R, et al. Prospect of mesenchymal stem cells in therapy of osteoporosis: A review. J Cell Physiol, 2019, 234(6): 8570-8578.
4.	Zuo R, Liu M, Wang Y, et al. BM-MSC-derived exosomes alleviate radiation-induced bone loss by restoring the function of recipient BM-MSCs and activating Wnt/β-catenin signaling. Stem Cell Res Ther, 2019, 10(1): 30. doi: 10.1186/s13287-018-1121-9.
5.	Xie X, Xiong Y, Panayi AC, et al. Exosomes as a novel approach to reverse osteoporosis: a review of the literature. Front Bioeng Biotechnol, 2020, 8: 594247. doi: 10.3389/fbioe.2020.594247.
6.	Chen C, Wang D, Moshaverinia A, et al. Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Res, 2017, 27(4): 559-577.
7.	Song H, Li X, Zhao Z, et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett, 2019, 19(5): 3040-3048.
8.	Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 2017, 546(7659): 498-503.
9.	Mendt M, Kamerkar S, Sugimoto H, et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight, 2018, 3(8): e99263. doi: 10.1172/jci.insight.99263.
10.	Yang J, Bi L, He X, et al. Follicular helper T cell derived exosomes promote B cell proliferation and differentiation in antibody-mediated rejection after renal transplantation. Biomed Res Int, 2019, 2019: 6387924. doi: 10.1155/2019/6387924.
11.	Cui S, Cheng Z, Qin W, et al. Exosomes as a liquid biopsy for lung cancer. Lung Cancer, 2018, 116: 46-54.
12.	Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci, 2018, 75(2): 193-208.
13.	Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem, 2019, 88: 487-514.
14.	Pethő A, Chen Y, George A. Exosomes in extracellular matrix bone biology. Curr Osteoporos Rep, 2018, 16(1): 58-64.
15.	Kalani A, Tyagi A, Tyagi N. Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol, 2014, 49(1): 590-600.
16.	Lindenbergh MFS, Wubbolts R, Borg EGF, et al. Dendritic cells release exosomes together with phagocytosed pathogen; potential implications for the role of exosomes in antigen presentation. J Extracell Vesicles, 2020, 9(1): 1798606. doi: 10.1080/20013078.2020.1798606.
17.	Lässer C, Eldh M, Lötvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp, 2012, (59): e3037. doi: 10.3791/3037.
18.	Li Y, Syed J, Sugiyama H. RNA-DNA triplex formation by long noncoding RNAs. Cell Chem Biol, 2016, 23(11): 1325-1333.
19.	Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl), 2013, 91(4): 431-437.
20.	Yu W, Zhong L, Yao L, et al. Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss. J Clin Invest, 2021, 131(2): e140214. doi: 10.1172/JCI140214.
21.	Huidrom S, Beg MA, Masood T. Post-menopausal osteoporosis and probiotics. Curr Drug Targets, 2021, 22(7): 816-822.
22.	Imerb N, Thonusin C, Chattipakorn N, et al. Aging, obese-insulin resistance, and bone remodeling. Mech Ageing Dev, 2020, 191: 111335. doi: 10.1016/j.mad.2020.111335.
23.	Askenase PW. Ancient evolutionary origin and properties of universally produced natural exosomes contribute to their therapeutic superiority compared to artificial nanoparticles. Int J Mol Sci, 2021, 22(3): 1429. doi: 10.3390/ijms22031429.
24.	Record M, Carayon K, Poirot M, et al. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta, 2014, 1841(1): 108-120.
25.	Deng P, Yuan Q, Cheng Y, et al. Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging. Cell Stem Cell, 2021, 28(6): 1057-1073.
26.	Zhao P, Xiao L, Peng J, et al. Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway. Eur Rev Med Pharmacol Sci, 2018, 22(12): 3962-3970.
27.	Xu JF, Yang GH, Pan XH, et al. Altered microRNA expression profile in exosomes during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. PLoS One, 2014, 9(12): e114627. doi: 10.1371/journal.pone.0114627.
28.	Tang L, Lu W, Huang J, et al. miR-144 promotes the proliferation and differentiation of bone mesenchymal stem cells by downregulating the expression of SFRP1. Mol Med Rep, 2019, 20(1): 270-280.
29.	Fu YC, Zhao SR, Zhu BH, et al. MiRNA-27a-3p promotes osteogenic differentiation of human mesenchymal stem cells through targeting ATF3. Eur Rev Med Pharmacol Sci, 2019, 23(3 Suppl): 73-80.
30.	Zhang Y, Cao X, Li P, et al. microRNA-935-modified bone marrow mesenchymal stem cells-derived exosomes enhance osteoblast proliferation and differentiation in osteoporotic rats. Life Sci, 2021, 272: 119204. doi: 10.1016/j.lfs.2021.119204.
31.	Wang Q, Wang CH, Meng Y. microRNA-1297 promotes the progression of osteoporosis through regulation of osteogenesis of bone marrow mesenchymal stem cells by targeting WNT5A. Eur Rev Med Pharmacol Sci, 2019, 23(11): 4541-4550.
32.	Yang X, Yang J, Lei P, et al. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis. Aging (Albany NY), 2019, 11(20): 8777-8791.
33.	Huynh N, VonMoss L, Smith D, et al. Characterization of regulatory extracellular vesicles from osteoclasts. J Dent Res, 2016, 95(6): 673-679.
34.	Li D, Liu J, Guo B, et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun, 2016, 7: 10872. doi: 10.1038/ncomms10872.
35.	Zhao C, Sun W, Zhang P, et al. miR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway. RNA Biol, 2015, 12(3): 343-353.
36.	Sun W, Zhao C, Li Y, et al. Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity. Cell Discov, 2016, 2: 16015. doi: 10.1038/celldisc.2016.15.
37.	Wei Y, Tang C, Zhang J, et al. Extracellular vesicles derived from the mid-to-late stage of osteoblast differentiation markedly enhance osteogenesis in vitro and in vivo. Biochem Biophys Res Commun, 2019, 514(1): 252-258.
38.	Cui Y, Luan J, Li H, et al. Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression. FEBS Lett, 2016, 590(1): 185-192.
39.	Deng L, Wang Y, Peng Y, et al. Osteoblast-derived microvesicles: A novel mechanism for communication between osteoblasts and osteoclasts. Bone, 2015, 79: 37-42.
40.	Morrell AE, Brown GN, Robinson ST, et al. Mechanically induced Ca²⁺ oscillations in osteocytes release extracellular vesicles and enhance bone formation. Bone Res, 2018, 6: 6. doi: 10.1038/s41413-018-0007-x.
41.	Qin Y, Peng Y, Zhao W, et al. Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication. J Biol Chem, 2017, 292(26): 11021-11033.
42.	Sato M, Suzuki T, Kawano M, et al. Circulating osteocyte-derived exosomes contain miRNAs which are enriched in exosomes from MLO-Y4 cells. Biomed Rep, 2017, 6(2): 223-231.
43.	Li J, Guo Y, Chen YY, et al. miR-124-3p increases in high glucose induced osteocyte-derived exosomes and regulates galectin-3 expression: A possible mechanism in bone remodeling alteration in diabetic periodontitis. FASEB J, 2020, 34(11): 14234-14249.
44.	Xiong Y, Chen L, Yan C, et al. M2 Macrophagy-derived exosomal miRNA-5106 induces bone mesenchymal stem cells towards osteoblastic fate by targeting salt-inducible kinase 2 and 3. J Nanobiotechnology, 2020, 18(1): 66. doi: 10.1186/s12951-020-00622-5.
45.	Xia Y, He XT, Xu XY, et al. Exosomes derived from M0, M1 and M2 macrophages exert distinct influences on the proliferation and differentiation of mesenchymal stem cells. Peer J, 2020, 8: e8970. doi: 10.7717/peerj.8970.
46.	Weilner S, Keider V, Winter M, et al. Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles. Aging (Albany NY), 2016, 8(1): 16-33.
47.	Li F, Chung H, Reddy SV, et al. Annexin Ⅱ stimulates RANKL expression through MAPK. J Bone Miner Res, 2005, 20(7): 1161-1167.
48.	Jia Y, Zhu Y, Qiu S, et al. Exosomes secreted by endothelial progenitor cells accelerate bone regeneration during distraction osteogenesis by stimulating angiogenesis. Stem Cell Res Ther, 2019, 10(1): 12. doi: 10.1186/s13287-018-1115-7.
49.	Qi X, Zhang J, Yuan H, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci, 2016, 12(7): 836-849.
50.	Zhang J, Liu X, Li H, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther, 2016, 7(1): 136. doi: 10.1186/s13287-016-0391-3.
51.	Hu Y, Zhang Y, Ni CY, et al. Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism. Theranostics, 2020, 10(5): 2293-2308.
52.	Yang BC, Kuang MJ, Kang JY, et al. Human umbilical cord mesenchymal stem cell-derived exosomes act via the miR-1263/Mob1/Hippo signaling pathway to prevent apoptosis in disuse osteoporosis. Biochem Biophys Res Commun, 2020, 524(4): 883-889.
53.	Zhang L, Wang Q, Su H, et al. Exosomes from adipose derived mesenchymal stem cells alleviate diabetic osteoporosis in rats through suppressing NLRP3 inflammasome activation in osteoclasts. J Biosci Bioeng, 2021, 131(6): 671-678.
54.	Ren L, Song ZJ, Cai QW, et al. Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. Biochem Biophys Res Commun, 2019, 508(1): 138-144.
55.	Mehryab F, Rabbani S, Shahhosseini S, et al. Exosomes as a next-generation drug delivery system: An update on drug loading approaches, characterization, and clinical application challenges. Acta Biomater, 2020, 113: 42-62.
56.	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): 20884-20892.
57.	Ma ZJ, Yang JJ, Lu YB, et al. Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine. World J Stem Cells, 2020, 12(8): 814-840.
58.	Chen M, Li Y, Lv H, et al. Quantitative proteomics and reverse engineer analysis identified plasma exosome derived protein markers related to osteoporosis. J Proteomics, 2020, 228: 103940. doi: 10.1016/j.jprot.2020.103940.

1. Johnston CB, Dagar M. Osteoporosis in older adults. Med Clin North Am, 2020, 104(5): 873-884.
2. Tsai JN, Lee H, David NL, et al. Combination denosumab and high dose teriparatide for postmenopausal osteoporosis (DATA-HD): a randomised, controlled phase 4 trial. Lancet Diabetes Endocrinol, 2019, 7(10): 767-775.
3. Aghebati-Maleki L, Dolati S, Zandi R, et al. Prospect of mesenchymal stem cells in therapy of osteoporosis: A review. J Cell Physiol, 2019, 234(6): 8570-8578.
4. Zuo R, Liu M, Wang Y, et al. BM-MSC-derived exosomes alleviate radiation-induced bone loss by restoring the function of recipient BM-MSCs and activating Wnt/β-catenin signaling. Stem Cell Res Ther, 2019, 10(1): 30. doi: 10.1186/s13287-018-1121-9.
5. Xie X, Xiong Y, Panayi AC, et al. Exosomes as a novel approach to reverse osteoporosis: a review of the literature. Front Bioeng Biotechnol, 2020, 8: 594247. doi: 10.3389/fbioe.2020.594247.
6. Chen C, Wang D, Moshaverinia A, et al. Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Res, 2017, 27(4): 559-577.
7. Song H, Li X, Zhao Z, et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett, 2019, 19(5): 3040-3048.
8. Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 2017, 546(7659): 498-503.
9. Mendt M, Kamerkar S, Sugimoto H, et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight, 2018, 3(8): e99263. doi: 10.1172/jci.insight.99263.
10. Yang J, Bi L, He X, et al. Follicular helper T cell derived exosomes promote B cell proliferation and differentiation in antibody-mediated rejection after renal transplantation. Biomed Res Int, 2019, 2019: 6387924. doi: 10.1155/2019/6387924.
11. Cui S, Cheng Z, Qin W, et al. Exosomes as a liquid biopsy for lung cancer. Lung Cancer, 2018, 116: 46-54.
12. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci, 2018, 75(2): 193-208.
13. Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem, 2019, 88: 487-514.
14. Pethő A, Chen Y, George A. Exosomes in extracellular matrix bone biology. Curr Osteoporos Rep, 2018, 16(1): 58-64.
15. Kalani A, Tyagi A, Tyagi N. Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol, 2014, 49(1): 590-600.
16. Lindenbergh MFS, Wubbolts R, Borg EGF, et al. Dendritic cells release exosomes together with phagocytosed pathogen; potential implications for the role of exosomes in antigen presentation. J Extracell Vesicles, 2020, 9(1): 1798606. doi: 10.1080/20013078.2020.1798606.
17. Lässer C, Eldh M, Lötvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp, 2012, (59): e3037. doi: 10.3791/3037.
18. Li Y, Syed J, Sugiyama H. RNA-DNA triplex formation by long noncoding RNAs. Cell Chem Biol, 2016, 23(11): 1325-1333.
19. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl), 2013, 91(4): 431-437.
20. Yu W, Zhong L, Yao L, et al. Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss. J Clin Invest, 2021, 131(2): e140214. doi: 10.1172/JCI140214.
21. Huidrom S, Beg MA, Masood T. Post-menopausal osteoporosis and probiotics. Curr Drug Targets, 2021, 22(7): 816-822.
22. Imerb N, Thonusin C, Chattipakorn N, et al. Aging, obese-insulin resistance, and bone remodeling. Mech Ageing Dev, 2020, 191: 111335. doi: 10.1016/j.mad.2020.111335.
23. Askenase PW. Ancient evolutionary origin and properties of universally produced natural exosomes contribute to their therapeutic superiority compared to artificial nanoparticles. Int J Mol Sci, 2021, 22(3): 1429. doi: 10.3390/ijms22031429.
24. Record M, Carayon K, Poirot M, et al. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta, 2014, 1841(1): 108-120.
25. Deng P, Yuan Q, Cheng Y, et al. Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging. Cell Stem Cell, 2021, 28(6): 1057-1073.
26. Zhao P, Xiao L, Peng J, et al. Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway. Eur Rev Med Pharmacol Sci, 2018, 22(12): 3962-3970.
27. Xu JF, Yang GH, Pan XH, et al. Altered microRNA expression profile in exosomes during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. PLoS One, 2014, 9(12): e114627. doi: 10.1371/journal.pone.0114627.
28. Tang L, Lu W, Huang J, et al. miR-144 promotes the proliferation and differentiation of bone mesenchymal stem cells by downregulating the expression of SFRP1. Mol Med Rep, 2019, 20(1): 270-280.
29. Fu YC, Zhao SR, Zhu BH, et al. MiRNA-27a-3p promotes osteogenic differentiation of human mesenchymal stem cells through targeting ATF3. Eur Rev Med Pharmacol Sci, 2019, 23(3 Suppl): 73-80.
30. Zhang Y, Cao X, Li P, et al. microRNA-935-modified bone marrow mesenchymal stem cells-derived exosomes enhance osteoblast proliferation and differentiation in osteoporotic rats. Life Sci, 2021, 272: 119204. doi: 10.1016/j.lfs.2021.119204.
31. Wang Q, Wang CH, Meng Y. microRNA-1297 promotes the progression of osteoporosis through regulation of osteogenesis of bone marrow mesenchymal stem cells by targeting WNT5A. Eur Rev Med Pharmacol Sci, 2019, 23(11): 4541-4550.
32. Yang X, Yang J, Lei P, et al. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis. Aging (Albany NY), 2019, 11(20): 8777-8791.
33. Huynh N, VonMoss L, Smith D, et al. Characterization of regulatory extracellular vesicles from osteoclasts. J Dent Res, 2016, 95(6): 673-679.
34. Li D, Liu J, Guo B, et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun, 2016, 7: 10872. doi: 10.1038/ncomms10872.
35. Zhao C, Sun W, Zhang P, et al. miR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway. RNA Biol, 2015, 12(3): 343-353.
36. Sun W, Zhao C, Li Y, et al. Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity. Cell Discov, 2016, 2: 16015. doi: 10.1038/celldisc.2016.15.
37. Wei Y, Tang C, Zhang J, et al. Extracellular vesicles derived from the mid-to-late stage of osteoblast differentiation markedly enhance osteogenesis in vitro and in vivo. Biochem Biophys Res Commun, 2019, 514(1): 252-258.
38. Cui Y, Luan J, Li H, et al. Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression. FEBS Lett, 2016, 590(1): 185-192.
39. Deng L, Wang Y, Peng Y, et al. Osteoblast-derived microvesicles: A novel mechanism for communication between osteoblasts and osteoclasts. Bone, 2015, 79: 37-42.
40. Morrell AE, Brown GN, Robinson ST, et al. Mechanically induced Ca²⁺ oscillations in osteocytes release extracellular vesicles and enhance bone formation. Bone Res, 2018, 6: 6. doi: 10.1038/s41413-018-0007-x.
41. Qin Y, Peng Y, Zhao W, et al. Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication. J Biol Chem, 2017, 292(26): 11021-11033.
42. Sato M, Suzuki T, Kawano M, et al. Circulating osteocyte-derived exosomes contain miRNAs which are enriched in exosomes from MLO-Y4 cells. Biomed Rep, 2017, 6(2): 223-231.
43. Li J, Guo Y, Chen YY, et al. miR-124-3p increases in high glucose induced osteocyte-derived exosomes and regulates galectin-3 expression: A possible mechanism in bone remodeling alteration in diabetic periodontitis. FASEB J, 2020, 34(11): 14234-14249.
44. Xiong Y, Chen L, Yan C, et al. M2 Macrophagy-derived exosomal miRNA-5106 induces bone mesenchymal stem cells towards osteoblastic fate by targeting salt-inducible kinase 2 and 3. J Nanobiotechnology, 2020, 18(1): 66. doi: 10.1186/s12951-020-00622-5.
45. Xia Y, He XT, Xu XY, et al. Exosomes derived from M0, M1 and M2 macrophages exert distinct influences on the proliferation and differentiation of mesenchymal stem cells. Peer J, 2020, 8: e8970. doi: 10.7717/peerj.8970.
46. Weilner S, Keider V, Winter M, et al. Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles. Aging (Albany NY), 2016, 8(1): 16-33.
47. Li F, Chung H, Reddy SV, et al. Annexin Ⅱ stimulates RANKL expression through MAPK. J Bone Miner Res, 2005, 20(7): 1161-1167.
48. Jia Y, Zhu Y, Qiu S, et al. Exosomes secreted by endothelial progenitor cells accelerate bone regeneration during distraction osteogenesis by stimulating angiogenesis. Stem Cell Res Ther, 2019, 10(1): 12. doi: 10.1186/s13287-018-1115-7.
49. Qi X, Zhang J, Yuan H, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci, 2016, 12(7): 836-849.
50. Zhang J, Liu X, Li H, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther, 2016, 7(1): 136. doi: 10.1186/s13287-016-0391-3.
51. Hu Y, Zhang Y, Ni CY, et al. Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism. Theranostics, 2020, 10(5): 2293-2308.
52. Yang BC, Kuang MJ, Kang JY, et al. Human umbilical cord mesenchymal stem cell-derived exosomes act via the miR-1263/Mob1/Hippo signaling pathway to prevent apoptosis in disuse osteoporosis. Biochem Biophys Res Commun, 2020, 524(4): 883-889.
53. Zhang L, Wang Q, Su H, et al. Exosomes from adipose derived mesenchymal stem cells alleviate diabetic osteoporosis in rats through suppressing NLRP3 inflammasome activation in osteoclasts. J Biosci Bioeng, 2021, 131(6): 671-678.
54. Ren L, Song ZJ, Cai QW, et al. Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. Biochem Biophys Res Commun, 2019, 508(1): 138-144.
55. Mehryab F, Rabbani S, Shahhosseini S, et al. Exosomes as a next-generation drug delivery system: An update on drug loading approaches, characterization, and clinical application challenges. Acta Biomater, 2020, 113: 42-62.
56. 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): 20884-20892.
57. Ma ZJ, Yang JJ, Lu YB, et al. Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine. World J Stem Cells, 2020, 12(8): 814-840.
58. Chen M, Li Y, Lv H, et al. Quantitative proteomics and reverse engineer analysis identified plasma exosome derived protein markers related to osteoporosis. J Proteomics, 2020, 228: 103940. doi: 10.1016/j.jprot.2020.103940.

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Research progress of exosomes in treatment of osteoporosis

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