Skip to main content
SpringerLink
Log in

The Macrophage’s Role on Bone Remodeling and Osteogenesis: a Systematic Review

  • Review Paper
  • Published:
Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Macrophages are one of the most abundant immune cells in the human body. They have several roles and functions in the body; however, their role in bone osteogenesis and remodulation has yet to be accurately determined. Thus, this systematic review aimed to determine and explain the macrophages’ role associated with remodeling and osteogenesis. Electronic search was conducted through MEDLINE (PubMed) and Web of Science (WoS), with the following focused question “What is the real macrophages’ role in the bone remodeling and osteogenesis and what would be the conditions to trigger the behavior?” After initial screening of 7051 articles, 31 were remained for full-text reading. Then, after revision and evaluation, 25 articles were included for the final qualitative analysis. Macrophages can be divided into inflammatory M1 macrophages and anti-inflammatory M2 macrophages. M1 and M2 act in a fracture and release proinflammatory cytokines recruiting cells, such as mesenchymal stem cells (MSCs), and increase osteoclast activity. After a few days, the inflammatory process stops, and M1 macrophages differentiate to M2 macrophages in the presence of IL-4. M2 macrophages release anti-inflammatory cytokines, upregulating RUNX-2 in MSCs, who consequently are differentiated to osteoblasts. These cells will produce bone matrix (osteocalcin, osteopontin, and collagen I), building/repairing the area. Based on the information gathered, it was possible to conclude that macrophages have a crucial role within osteogenesis, and both M1 and M2 macrophages are essential to make the inflammatory and remodeling phase have an adequate formation/recovery.

Graphical Abstract

Summarization of all findings related to this systematic review, reporting the phases, involvement, and behavior of macrophages and other constituents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Marotti G, Ferretti M, Palumbo C, Benincasa M. Static and dynamic bone formation and the mechanism of collagen fiber orientation. Bone. 1999;25:156.

    Google Scholar 

  2. Ferretti M, Palumbo C, Contri M, Marotti G. Static and dynamic osteogenesis: two different types of bone formation. Anat Embryol. 2002;206:21–9.

    Article  Google Scholar 

  3. El-Rashidy AA, Roether JA, Harhaus L, Kneser U, Boccaccini AR. Regenerating bone with bioactive glass scaffolds: a review of in vivo studies in bone defect models. Acta Biomater. 2017;62:1–28.

    Article  CAS  PubMed  Google Scholar 

  4. Fabris ALD, Faverani LP, Gomes-Ferreira PHS, Polo TOB, Santiago-Junior JF, Okamoto R. Bone repair access of BoneCeramic (TM) in 5-mm defects: study on rat calvaria. J Appl Oral Sci. 2018;26:e20160531.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Garcia-Gareta E, Coathup M-J, Blunn GW. Osteoinduction of bone grafting materials for bone repair and regeneration. Bone. 2015;81:112–21.

    Article  CAS  PubMed  Google Scholar 

  6. Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15:786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mouw JK, Ou GQ, Weaver VM. Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol. 2014;15:771–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mansour A, Mezour MA, Badran Z, Tamimi F. Extracellular matrices for bone regeneration: a literature review. Tissue Eng Part A. 2017;23:1436–51.

    Article  PubMed  Google Scholar 

  9. Franz-Odendaal TA, Hall BK, Witten PE. Buried alive: how osteoblasts become osteocytes. Dev Dyn. 2006;235:176–90.

    Article  CAS  PubMed  Google Scholar 

  10. Aarden EM, Burger EH, Nijweide PJ. Function of osteocytes in bone. J Cell Biochem. 1994;55:287–99.

    Article  CAS  PubMed  Google Scholar 

  11. Wang S, Xiao L, Prasadam I, Crawford R, Zhou Y, Xiao Y. Inflammatory macrophages interrupt osteocyte maturation and mineralization via regulating the Notch signaling pathway. Mol Med. 2022;28:102. https://doi.org/10.1186/s10020-022-00530-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gordon S. Elie Metchnikoff, the man and the myth. J Innate Immun. 2016;8:223–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Remmerie A, Scotta CL. Macrophages and lipid metabolism. Cell Immunol. 2018;330:27–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. Kupffer cells in the liver. Compr Physiol. 2013;3:785–97.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chang MK, Raggatt L-J, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, Maylin ER, Ripoll VM, Hume DA, Pettit RA. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol. 2008;181:1232–44.

    Article  CAS  PubMed  Google Scholar 

  16. Cho S-K. Role of osteal macrophages in bone metabolism. J Pathol Transl Med. 2015;49:102–4.

    Article  Google Scholar 

  17. Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci. 2018;19:1801.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gu Q, Yang H, Shi Q. Macrophages and bone inflammation. J Orthop Translat. 2017;10:86–93.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wu X, Xu W, Feng X, He Y, Liu X, Gao Y. TNF-α mediated inflammatory macrophage polarization contributes to the pathogenesis of steroid-induced osteonecrosis in mice. Int J Immunopathol Pharmacol. 2015;28:351–61.

    Article  CAS  PubMed  Google Scholar 

  20. Duque GA, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491.

    Google Scholar 

  21. Champagne CM, Takebe J, Offenbacher S, Cooper LF. Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone. 2002;30:26–31.

    Article  CAS  PubMed  Google Scholar 

  22. Sinder BP, Pettit AR, McCauley LK. Macrophages: their emerging roles in bone. J Bone Miner Res. 2015;30:2140–9.

    Article  PubMed  Google Scholar 

  23. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Baht GS, Vi L, Alman BA. The role of the immune cells in fracture healing. Curr Osteoporos Rep. 2018;16:138–45.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vi L, Baht GS, Soderblom EJ, Whetstone H, Wei Q, Furman B, Puviindran V, Nadesan P, Foster M, Poon R, White JP, Yahara Y, Ng A, Barrientos T, Grynpas M, Mosely MA, Alman BA. Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice. Nat Commun. 2018;9:5191.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Vi L, Baht GS, Whetstone H, Ng A, Wei Q, Poon R, Mylvaganam S, Grynpas M, Alman BA. Macrophages promote osteoblastic differentiation in-vivo: implications in fracture repair and bone homeostasis. J Bone Miner Res. 2015;30:1090–102.

    Article  CAS  PubMed  Google Scholar 

  27. Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther. 2016;7:44.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Romero-Lopez M, Li Z, Rhee C, Maruyama M, Pajarinen J, O’Donnell B, Lin T-H, Lo C-W, Hanlon J, Dubowitz R, Yao Z, Bunnell BA, Lin H, Tuan RS, Goodman SB. Macrophage effects on mesenchymal stem cell osteogenesis in a three-dimensional in vitro bone model. Tissue Eng Part A. 2020;26:1099–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gong L, Zhao Y, Zhang Y, Ruan Z. The macrophage polarization regulates MSC osteoblast differentiation in vitro. Ann Clin Lab Sci. 2016;46:65–71.

    CAS  PubMed  Google Scholar 

  30. Lu LY, Loi F, Nathan K, Lin TH, Pajarinen J, Gibon E, Nabeshima A, Cordova L, Jämsen E, Yao Z, Goodman SB. Pro-inflammatory M1 macrophages promote osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway. J Orthop Res. 2017;35:2378–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xiong Y, Chen L, Yan C, Zhou W, Yu T, Sun Y, Cao F, Xue H, Hu Y, Chen D, Mi B, Liu G. 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;18:66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ehnert S, Linnemann C, Aspera-Werz RH, Bykova D, Biermann S, Fecht L, De Zwart PM, Nussler AK, Stuby F. Immune cell induced migration of osteoprogenitor cells is mediated by TGF-beta dependent upregulation of NOX4 and activation of focal adhesion kinase. Int J Mol Sci. 2018;19:2239.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhao SJ, Kong FQ, Jie J, Li Q, Liu H, Xu A-D, Yang Y-Q, Jiang B, Wang D-D, Zhou Z-Q, Tang P-Y, Chen J, Wang Q, Zhou Z, Chen Q, Yin G-Y, Zhang H-W, Fan J. Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3beta/beta-catenin pathway. Theranostics. 2020;10:17–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pajarinen J, Lin T, Gibon E, Kohno Y, Maruyama M, Nathan K, Lu L, Yao Z, Goodman SB. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials. 2019;196:80–9.

    Article  CAS  PubMed  Google Scholar 

  35. Lin T, Pajarinen J, Nabeshima A, Lu L, Nathan K, Jamsen E, Yao Z, Goodman SB. Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis. Stem Cell Res Ther. 2017;8:277.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Nathan K, Lu LYL, Lin T, Pajarinen J, Jämsen E, Huang J-F, Romero-Lopez M, Maruyama M, Kohno Y, Yao Z, Goodman SB. Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone Joint Res. 2019;8:481–8.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Raggatt LJ, Wullschleger ME, Alexander KA, Wu AC, Millard SM, Kaur S, Maugham ML, Gregory LS, Steck R, Pettit AR. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am J Pathol. 2014;184:3192–204.

    Article  CAS  PubMed  Google Scholar 

  38. Lee J, Byun H, Perikamana SKM, Lee S, Shin H. Current advances in immunomodulatory biomaterials for bone regeneration. Adv Healthc Mater. 2019;8:e1801106.

    Article  PubMed  Google Scholar 

  39. Wasnik S, Rundle CH, Baylink DJ, Yazdi MS, Carreon EE, Xu Y, Qin X. Lau K-HW, Tang X, 1,25-dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites. JCI Insight. 2018;3:e98773.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lee B, Iwaniec UT, Turner RT, Lin YW, Clarke BL, Gingery A, Wei LN. RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis. JCI Insight. 2017;2:e90517.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang N, Liu X, Shi L, Liu Y, Guo S, Liu W, Li X, Meng J, Ma X, Guo Z. Identification of a prolonged action molecular GLP-1R agonist for the treatment of femoral defects. Biomater Sci. 2020;8:1604–14.

    Article  CAS  PubMed  Google Scholar 

  42. Annamalai RT, Turner PA, Carson WFT, Levi B, Kunkel S, Stegemann JP. Harnessing macrophage-mediated degradation of gelatin microspheres for spatiotemporal control of BMP2 release. Biomaterials. 2018;161:216–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang J, Liu D, Guo B, Yang X, Chen X, Zhu X, Fan Y, Zhang X. Role of biphasic calcium phosphate ceramic-mediated secretion of signaling molecules by macrophages in migration and osteoblastic differentiation of MSCs. Acta Biomater. 2017;51:447–60.

    Article  CAS  PubMed  Google Scholar 

  44. Niu Y, Wang L, Yu N, Xing P, Wang Z, Zhong Z, Feng Y, Dong L, Wang C. An “all-in-one” scaffold targeting macrophages to direct endogenous bone repair in situ. Acta Biomater. 2020;111:153–69.

    Article  CAS  PubMed  Google Scholar 

  45. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2018;9:7204–18.

    Article  PubMed  Google Scholar 

  46. Niedermair T, Straub RH, Brochhausen C, Grässel S. Impact of the sensory and sympathetic nervous system on fracture healing in ovariectomized mice. Int J Mol Sci 2020;21(2):405. https://doi.org/10.3390/ijms21020405.

  47. Chow SK, Chim YN, Wang J, Zhang N, Wong RM, Tang N, et al. Vibration treatment modulates macrophage polarisation and enhances early inflammatory response in oestrogen-deficient osteoporotic-fracture healing. Eur Cell Mater 2019;38:228-45.

  48. Cui Y, Fu S, Hou T, Wu X. Endothelial progenitor cells enhance the migration and osteoclastic differentiation of bone marrow-derived macrophages in vitro and in a mouse femur fracture model through Talin-1. Cell Physiol Biochem 2018;49(2):555-564. https://doi.org/10.1159/000492993.

  49. Nicolin V, Baldini G, De Iaco D, Bortul R, Turco G, Nori SL. Looking for calcium phosphate composite suitable to study osteoclast endocytosis: Preliminary observations. Transl Med UniSa. 2016;14:15-20.

  50. Guo J-P, Pan J-X, Xiong L, Xia W-F, Cui S, Xiong W-C. Iron chelation inhibits osteoclastic differentiation in vitro and in Tg2576 mouse model of Alzheimer's disease. PLoS One 2015;10(11):e0139395. https://doi.org/10.1371/journal.pone.0139395.

Download references

Author information

Authors and Affiliations

  1. Biomedical Sciences, Universidade Católica Portuguesa, Viseu, Portugal

    João Maria Orvalho

  2. DDS; Private Clinician, Ann Arbor, USA

    Juliana Campos Hasse Fernandes

  3. Periodontics and Oral Medicine Department, University of Michigan, 1011 North University Ave, Ann Arbor, MI, 48109, USA

    Rogerio Moraes Castilho & Gustavo Vicentis Oliveira Fernandes

Authors
  1. João Maria Orvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juliana Campos Hasse Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rogerio Moraes Castilho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gustavo Vicentis Oliveira Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gustavo Vicentis Oliveira Fernandes.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Orvalho, J.M., Fernandes, J.C.H., Moraes Castilho, R. et al. The Macrophage’s Role on Bone Remodeling and Osteogenesis: a Systematic Review. Clinic Rev Bone Miner Metab 21, 1–13 (2023). https://doi.org/10.1007/s12018-023-09286-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12018-023-09286-9

Keywords

Search

Navigation