Int J Stomatol ›› 2023, Vol. 50 ›› Issue (1): 120-126.doi: 10.7518/gjkq.2023015

• Reviews • Previous Articles    

Research progress on the regulation of bone remodeling by macrophage-derived exosomes

Liu Yi(),Liu Yi.()   

  1. Dept. of Orthodontics, The Affiliated Hospital of Stomatology, China Medical University, Shenyang 110013, China
  • Received:2022-06-06 Revised:2022-10-17 Online:2023-01-01 Published:2023-01-09
  • Contact: Yi Liu,Yi. Liu;
  • Supported by:
    Liaoning Province Key Research and Development Plan Project(2020JH2/10300038)


Macrophages are the major components of human innate immunity and are closely related to bone tissue. Exosomes are nanoscale vesicles released by all cells, thus carrying nucleic acid and other information from the source cells to organize the function of target cells. Studies have demonstrated that macrophage-derived exosomes can effectively regulate bone remodeling, modulate the microenvironment in a variety of ways, and then affect osteogenesis. This paper summarizes the research progress onthe effect of macrophage-derived exosomes on bone remodeling to provide a reference for the development of therapeutic strategies.

Key words: macrophages, exosome, bone remodeling, inflammation

CLC Number: 

  • R 783.5


Fig 1

The regulation of M1 macrophages-derived exosomes on the signal pathway of bone remodeling"

Fig 2

The regulation of M2 macrophages-derived exosomes on the signal pathway of bone remodeling"

1 Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective[J]. Annu Rev Immunol, 2009, 27: 451-483.
2 Saradna A, Do DC, Kumar S, et al. Macrophage polarization and allergic asthma[J]. Transl Res, 2018, 191: 1-14.
3 McDonald MK, Tian YZ, Qureshi RA, et al. Functional significance of macrophage-derived exosomes in inflammation and pain[J]. Pain, 2014, 155(8): 1527-1539.
4 Mountziaris PM, Spicer PP, Kasper FK, et al. Harnessing and modulating inflammation in strategies for bone regeneration[J]. Tissue Eng Part B Rev, 2011, 17(6): 393-402.
5 Li ZY, Wang YF, Li SL, et al. Exosomes derived from M2 macrophages facilitate osteogenesis and reduce adipogenesis of BMSCs[J]. Front Endocrinol (Lausanne), 2021, 12: 680328.
6 Schlundt C, El Khassawna T, Serra A, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification[J]. Bone, 2018, 106: 78-89.
7 Yona S, Kim KW, Wolf Y, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis[J]. Immunity, 2013, 38(1): 79-91.
8 Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease[J]. J Cell Physiol, 2018, 233(9): 6425-6440.
9 Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas[J]. J Clin Invest, 2012, 122(3): 787-795.
10 Arabpour M, Saghazadeh A, Rezaei N. Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes[J]. Int Immunopharmacol, 2021, 97: 107823.
11 Shrivastava R, Shukla N. Attributes of alternatively activated(M2) macrophages[J]. Life Sci, 2019, 224: 222-231.
12 Salhotra A, Shah HN, Levi B, et al. Mechanisms of bone development and repair[J]. Nat Rev Mol Cell Biol, 2020, 21(11): 696-711.
13 Schlundt C, Fischer H, Bucher CH, et al. The multifaceted roles of macrophages in bone regeneration: a story of polarization, activation and time[J]. Acta Biomater, 2021, 133: 46-57.
14 Huang R, Wang X, Zhou YH, et al. RANKL-induced M1 macrophages are involved in bone formation[J]. Bone Res, 2017, 5: 17019.
15 Loi F, Córdova LA, Zhang R, et al. The effects of immunomodulation by macrophage subsets on osteogenesis in vitro [J]. Stem Cell Res Ther, 2016, 7: 15.
16 He D, Kou X, Yang R, et al. M1-like macrophage polarization promotes orthodontic tooth movement[J]. J Dent Res, 2015, 94(9): 1286-1294.
17 Wang XY, Ji QB, Hu WH, et al. Isobavachalcone prevents osteoporosis by suppressing activation of ERK and NF-κB pathways and M1 polarization of macrophages[J]. Int Immunopharmacol, 2021, 94: 107370.
18 Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease[J]. N Engl J Med, 2018, 379(22): 2180-2181.
19 Lötvall J, Hill AF, Hochberg F, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles[J]. J Extracell Vesicles, 2014, 3: 26913.
20 Akbar N, Paget D, Choudhury RP. Extracellular vesicles in innate immune cell programming[J]. Biomedicines, 2021, 9(7): 713.
21 Garzetti L, Menon R, Finardi A, et al. Activated macrophages release microvesicles containing polarized M1 or M2 mRNAs[J]. J Leukoc Biol, 2014, 95(5): 817-825.
22 Vizoso FJ, Eiro N, Cid S, et al. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine[J]. Int J Mol Sci, 2017, 18(9): E1852.
23 Liu SJ, Chen J, Shi J, et al. M1-like macrophage-derived exosomes suppress angiogenesis and exacerbate cardiac dysfunction in a myocardial infarction microenvironment[J]. Basic Res Cardiol, 2020, 115(2): 22.
24 Kang MY, Huang CC, Lu Y, et al. Bone regeneration is mediated by macrophage extracellular vesicles[J]. Bone, 2020, 141: 115627.
25 Ge XH, Tang PY, Rong YL, et al. Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury[J]. Redox Biol, 2021, 41: 101932.
26 Hu YK, Wang Y, Chen TH, et al. Exosome: function and application in inflammatory bone diseases[J]. Oxid Med Cell Longev, 2021, 2021: 6324912.
27 Pajarinen J, Lin T, Gibon E, et al. Mesenchymal stem cell-macrophage crosstalk and bone healing[J]. Biomaterials, 2019, 196: 80-89.
28 Paschalidi P, Gkouveris I, Soundia A, et al. The role of M1 and M2 macrophage polarization in progression of medication-related osteonecrosis of the jaw[J]. Clin Oral Investig, 2021, 25(5): 2845-2857.
29 Boldin MP, MicroRNAs Baltimore D., new effectors and regulators of NF-κB [J]. Immunol Rev, 2012, 246(1): 205-220.
30 Wang Z, Zhu H, Shi HT, et al. Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222/CDKN1B/CDKN1C pathway[J]. Cell Death Dis, 2019, 10(6): 422.
31 Qi YY, Zhu TT, Zhang TT, et al. M1 macrophage-derived exosomes transfer miR-222 to induce bone marrow mesenchymal stem cell apoptosis[J]. Lab Invest, 2021, 101(10): 1318-1326.
32 Yu L, Hu M, Cui X, et al. M1 macrophage-derived exosomes aggravate bone loss in postmenopausal osteoporosis via a microRNA-98/DUSP1/JNK axis[J]. Cell Biol Int, 2021, 45(12): 2452-2463.
33 Peng SS, Yan Y, Li R, et al. Extracellular vesicles from M1-polarized macrophages promote inflammation in the temporomandibular joint via miR-1246 activation of the Wnt/β-catenin pathway[J]. Ann N Y Acad Sci, 2021, 1503(1): 48-59.
34 Jimi E, Takakura N, Hiura F, et al. The role of NF-κB in physiological bone development and inflammatory bone diseases: is NF-κB inhibition “killing two birds with one stone” [J]. Cells, 2019, 8(12): E1636.
35 Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines[J]. Semin Immunol, 2014, 26(3): 253-266.
36 Wang PP, Wang HH, Huang QQ, et al. Exosomes from M1-polarized macrophages enhance paclitaxel antitumor activity by activating macrophages-mediated inflammation[J]. Theranostics, 2019, 9(6): 1714-1727.
37 He XT, Li X, Yin Y, et al. The effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells[J]. J Cell Mol Med, 2018, 22(2): 1302-1315.
38 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[J]. PeerJ, 2020, 8: e8970.
39 朱宸佑, 魏诗敏, 汪媛婧, 等. 巨噬细胞在骨组织修复中的研究进展[J]. 国际口腔医学杂志, 2018, 45(4): 444-448.
Zhu CY, Wei SM, Wang YJ, et al. Research progress on macrophage in bone tissue repair[J]. Int J Stomatol, 2018, 45(4): 444-448.
40 Wei F, Zhou YH, Wang J, et al. The immunomodulatory role of BMP-2 on macrophages to accelerate osteogenesis[J]. Tissue Eng Part A, 2018, 24(7/8): 584-594.
41 Yang YH, Guo ZY, Chen WW, et al. M2 macrophage-derived exosomes promote angiogenesis and growth of pancreatic ductal adenocarcinoma by targeting E2F2[J]. Mol Ther, 2021, 29(3): 1226-1238.
42 Bouchareychas L, Duong P, Covarrubias S, et al. Macrophage exosomes resolve atherosclerosis by regulating hematopoiesis and inflammation via microRNA cargo[J]. Cell Rep, 2020, 32(2): 107881.
43 Yu SH, Geng QQ, Pan QH, et al. miR-690, a Runx2-targeted miRNA, regulates osteogenic differentiation of C2C12 myogenic progenitor cells by targeting NF-kappaB p65[J]. Cell Biosci, 2016, 6: 10.
44 Zhang H, Zhao YY, Zhang Y, et al. Exosomes derived from macrophages upon cobalt ion stimulation promote angiogenesis[J]. Colloids Surf B Biointerfaces, 2021, 203: 111742.
45 Xu T, Luo YJ, Wang JX, et al. Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5[J]. J Nanobiotechnology, 2020, 18(1): 47.
46 Zhang D, Wu YF, Li ZH, et al. miR-144-5p, an exosomal miRNA from bone marrow-derived macrophage in type 2 diabetes, impairs bone fracture healing via targeting Smad1[J]. J Nanobiotechnology, 2021, 19(1): 226.
47 Huang XQ, Xiong XE, Liu J, et al. MicroRNAs-containing extracellular vesicles in bone remodeling: an emerging frontier[J]. Life Sci, 2020, 254: 117809.
48 He XT, Li X, Yin Y, et al. The effects of conditioned media generated by polarized macrophages on the ce-llular behaviours of bone marrow mesenchymal stem cells[J]. J Cell Mol Med, 2018, 22(2): 1302-1315.
49 Dou C, Ding N, Zhao CR, et al. Estrogen deficiency-mediated M2 macrophage osteoclastogenesis contributes to M1/M2 ratio alteration in ovariectomized osteoporotic mice[J]. J Bone Miner Res, 2018, 33(5): 899-908.
50 Wehrhan F, Moebius P, Amann K, et al. Macrophage and osteoclast polarization in bisphosphonate associated necrosis and osteoradionecrosis[J]. J Craniomaxillofac Surg, 2017, 45(6): 944-953.
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