Extensive bone fractures, which can seriously impact both health and quality of life, cannot easily heal naturally, especially if the patient has an underlying medical condition or is aging. The most promising approach to addressing such fractures is bone regeneration through bone tissue engineering. Bone regeneration is a complex process that consists of three distinct phases: inflammation, repair, and remodeling. Macrophages play a bridging role between the various cells involved in each stage of bone regeneration, interacting with different microenvironments and advancing the bone healing process. Although the origin and function of macrophages have been extensively studied, the mechanisms underlying their interaction with the bone healing microenvironment remain unexplored, including the association of microenvironmental changes with macrophage reprogramming and the role of macrophages in cells in the microenvironment. This review summarizes the bone regeneration process and recent advances in research on interactions between macrophages and the bone healing microenvironment and discusses novel biological strategies to promote bone regeneration by modulating macrophages for the treatment of bone injury and loss.
Impact statement
In this review, we focus on the relationship between the bone healing microenvironment and cells during the three stages of bone healing. We focused on the metabolic reprogramming of macrophages by the microenvironment, which in turn leads to alterations in their phenotype, as well as macrophages influencing components of the microenvironment through paracrine secretion. In addition, we present recent advances in the improvement of bone regeneration materials through macrophage modulation, which will be useful for subsequent research and clinical translation.
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References
1.
NoelSE, SantosMP, WrightNC. Racial and ethnic disparities in bone health and outcomes in the United States. J Bone Miner Res, 2021; 36(10):1881–1905; doi: 10.1002/jbmr.4417
2.
JanakiramC, DyeBA. A public health approach for prevention of periodontal disease. Periodontol 2000, 2020; 84(1):202–214; doi: 10.1111/prd.12337
3.
De la VegaRE, Atasoy-ZeybekA, PanosJA, et al.Gene therapy for bone healing: Lessons learned and new approaches. Transl Res, 2021; 236:1–16; doi: 10.1016/j.trsl.2021.04.009
4.
KalfasIH. Principles of bone healing. Neurosurg Focus, 2001; 10(4):E1; doi: 10.3171/foc.2001.10.4.2
5.
ZuraR, XiongZ, EinhornT, et al.Epidemiology of fracture nonunion in 18 human bones. JAMA Surg, 2016; 151(11):e162775; doi: 10.1001/jamasurg.2016.2775
6.
HortonJE, RaiszLG, SimmonsHA, et al.Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science, 1972; 177(4051):793–795; doi: 10.1126/science.177.4051.793
7.
MaruyamaM, RheeC, UtsunomiyaT, et al.Modulation of the inflammatory response and bone healing. Front Endocrinol (Lausanne), 2020; 11:386; doi: 10.3389/fendo.2020.00386
8.
ArronJR, ChoiY. Bone versus immune system. Nature, 2000; 408(6812):535–536; doi: 10.1038/35046196
9.
GraneyPL, Roohani-EsfahaniSI, ZreiqatH, et al.In vitro response of macrophages to ceramic scaffolds used for bone regeneration. J R Soc Interface, 2016; 13(120):20160346; doi: 10.1098/rsif.2016.0346
10.
ClaesL, RecknagelS, IgnatiusA. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol, 2012; 8(3):133–143; doi: 10.1038/nrrheum.2012.1
11.
SunY, LiJ, XieX, et al.Macrophage-osteoclast associations: Origin, polarization, and subgroups. Front Immunol, 2021; 12:778078; doi: 10.3389/fimmu.2021.778078
12.
PajarinenJ, LinT, GibonE, et al.Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019; 196:80–89; doi: 10.1016/j.biomaterials.2017.12.025
13.
ShiraziS, RavindranS, CooperLF. Topography-mediated immunomodulation in osseointegration; Ally or Enemy. Biomaterials, 2022; 291:121903; doi: 10.1016/j.biomaterials.2022.121903
14.
XieY, HuC, FengY, et al.Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration. Regen Biomater, 2020; 7(3):233–245; doi: 10.1093/rb/rbaa006
15.
LiJ, JiangX, LiH, et al.Tailoring materials for modulation of macrophage fate. Adv Mater, 2021; 33(12):e2004172; doi: 10.1002/adma.202004172
16.
MarsellR, EinhornTA. The biology of fracture healing. Injury, 2011; 42(6):551–555; doi: 10.1016/j.injury.2011.03.031
17.
CruessRL, DumontJ. Fracture healing. Can J Surg, 1975; 18(5):403–413.
18.
UderhardtS, MartinsAJ, TsangJS, et al.Resident macrophages cloak tissue microlesions to prevent neutrophil-driven inflammatory damage. Cell, 2019; 177(3):541–555.e17; doi: 10.1016/j.cell.2019.02.028
19.
NiuY, WangZ, ShiY, et al.Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches. Bioact Mater, 2021; 6(1):244–261; doi: 10.1016/j.bioactmat.2020.08.012
20.
TakeshitaS, KajiK, KudoA. Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res, 2000; 15(8):1477–1488; doi: 10.1359/jbmr.2000.15.8.1477
21.
GerlachBD, AmpomahPB, YurdagulAJr., et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab, 2021; 33(12):2445–2463.e8; doi: 10.1016/j.cmet.2021.10.015
22.
RemediosA. Bone and bone healing. Vet Clin North Am Small Anim Pract, 1999; 29(5):1029–1044, v; doi: 10.1016/s0195-5616(99)50101-0
23.
LoiF, CórdovaLA, PajarinenJ, et al.Inflammation, fracture and bone repair. Bone, 2016; 86:119–130; doi: 10.1016/j.bone.2016.02.020
24.
BatoonL, MillardSM, RaggattLJ, et al.Osteomacs and bone regeneration. Curr Osteoporos Rep, 2017; 15(4):385–395; doi: 10.1007/s11914-017-0384-x
25.
BianZ, GongY, HuangT, et al.Deciphering human macrophage development at single-cell resolution. Nature, 2020; 582(7813):571–576; doi: 10.1038/s41586-020-2316-7
26.
MassE, NimmerjahnF, KierdorfK, et al.Tissue-specific macrophages: How they develop and choreograph tissue biology. Nat Rev Immunol, 2023; 23:563–579; doi: 10.1038/s41577-023-00848-y
27.
MironRJ, BosshardtDD. OsteoMacs: Key players around bone biomaterials. Biomaterials, 2016; 82:1–19; doi: 10.1016/j.biomaterials.2015.12.017
28.
LiuZ, GuY, ChakarovS, et al.Fate Mapping via Ms4a3-expression history traces monocyte-derived cells. Cell, 2019; 178(6):1509–1525.e19; doi: 10.1016/j.cell.2019.08.009
29.
BabaeijandaghiF, ChengR, KajabadiN, et al.Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics. Sci Transl Med, 2022; 14(651):eabg7504; doi: 10.1126/scitranslmed.abg7504
30.
SunX, GaoJ, MengX, et al.Polarized macrophages in periodontitis: Characteristics, function, and molecular signaling. Front Immunol, 2021; 12:763334; doi: 10.3389/fimmu.2021.763334
31.
MillsCD, KincaidK, AltJM, et al.M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol, 2000; 164(12):6166–6173; doi: 10.4049/jimmunol.164.12.6166
32.
GongL, ZhaoY, ZhangY, et al.The macrophage polarization regulates MSC osteoblast differentiation in vitro. Ann Clin Lab Sci, 2016; 46(1):65–71.
ZhangY, BöseT, UngerRE, et al.Macrophage type modulates osteogenic differentiation of adipose tissue MSCs. Cell Tissue Res, 2017; 369(2):273–286; doi: 10.1007/s00441-017-2598-8
35.
WangLX, ZhangSX, WuHJ, et al.M2b macrophage polarization and its roles in diseases. J Leukoc Biol, 2019; 106(2):345–358; doi: 10.1002/jlb.3ru1018-378rr
36.
NagataS. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol, 2018; 36:489–517; doi: 10.1146/annurev-immunol-042617-053010
37.
YangH, BiermannM, BraunerJ, et al.New insights into neutrophil extracellular traps: Mechanisms of formation and role in inflammation. Front Immunol, 2016; 7:302; doi: 10.3389/fimmu.2016.00302
38.
MosserDM, EdwardsJP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol, 2008; 8(12):958–969; doi: 10.1038/nri2448
39.
DudaGN, GeisslerS, ChecaS, et al.The decisive early phase of bone regeneration. Nat Rev Rheumatol, 2023; 19(2):78–95; doi: 10.1038/s41584-022-00887-0
40.
DaleyJM, BrancatoSK, ThomayAA, et al.The phenotype of murine wound macrophages. J Leukoc Biol, 2010; 87(1):59–67; doi: 10.1189/jlb.0409236
41.
WillenborgS, LucasT, van LooG, et al.CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood, 2012; 120(3):613–625; doi: 10.1182/blood-2012-01-403386
ZecchiniV, PaupeV, Herranz-MontoyaI, et al.Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature, 2023; 615(7952):499–506; doi: 10.1038/s41586-023-05770-w
46.
KnipperJ, WillenborgS, BrinckmannJ, et al.Interleukin-4 receptor α signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity, 2015; 43(4):803–816; doi: 10.1016/j.immuni.2015.09.005
47.
WillenborgS, SaninD, JaisA, et al.Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab, 2021; 33(12):2398–2414.e9; doi: 10.1016/j.cmet.2021.10.004
48.
LiZ, MeyersC, ChangL, et al.Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Investig, 2019; 129(12):5137–5150; doi: 10.1172/jci128428
49.
MeyersC, LeeS, SonoT, et al.A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Reports, 2020; 31(8):107696; doi: 10.1016/j.celrep.2020.107696
50.
LiangB, WangH, WuD, et al.Macrophage M1/M2 polarization dynamically adapts to changes in microenvironment and modulates alveolar bone remodeling after dental implantation. J Leukoc Biol, 2021; 110(3):433–447; doi: 10.1002/jlb.1ma0121-001r
51.
KuleszaA, PaczekL, BurdzinskaA. The Role of COX-2 and PGE2 in the regulation of immunomodulation and other functions of mesenchymal stromal cells. Biomedicines, 2023; 11(2):445; doi: 10.3390/biomedicines11020445
52.
TanHY, WangN, LiS, et al.The reactive oxygen species in macrophage polarization: Reflecting its dual role in progression and treatment of human diseases. Oxid Med Cell Longev, 2016; 2016:2795090; doi: 10.1155/2016/2795090
53.
WangN, LiangH, ZenK. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol, 2014; 5:614; doi: 10.3389/fimmu.2014.00614
54.
LiuYC, ZouXB, ChaiYF, et al.Macrophage polarization in inflammatory diseases. Int J Biol Sci, 2014; 10(5):520–529; doi: 10.7150/ijbs.8879
55.
WillenborgS, InjarabianL, EmingSA. Role of macrophages in wound healing. Cold Spring Harb Perspect Biol, 2022; 14(12):a041216; doi: 10.1101/cshperspect.a041216
56.
BaoL, DouG, TianR, et al.Engineered neutrophil apoptotic bodies ameliorate myocardial infarction by promoting macrophage efferocytosis and inflammation resolution. Bioact Mater, 2022; 9:183–197; doi: 10.1016/j.bioactmat.2021.08.008
57.
HuangSC, EvertsB, IvanovaY, et al.Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol, 2014; 15(9):846–855; doi: 10.1038/ni.2956
58.
YurdagulAJr., SubramanianM, WangX, et al.Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury. Cell Metab, 2020; 31(3):518–533.e10; doi: 10.1016/j.cmet.2020.01.001
59.
JhaAK, HuangSC, SergushichevA, et al.Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity, 2015; 42(3):419–430; doi: 10.1016/j.immuni.2015.02.005
60.
WangA, LuanHH, MedzhitovR. An evolutionary perspective on immunometabolism. Science, 2019; 363(6423):eaar3932; doi: 10.1126/science.aar3932
61.
GautierEL, ChowA, SpanbroekR, et al.Systemic analysis of PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity. J Immunol, 2012; 189(5):2614–2624; doi: 10.4049/jimmunol.1200495
62.
MassE, BallesterosI, FarlikM, et al.Specification of tissue-resident macrophages during organogenesis. Science, 2016; 353(6304):aaf4238; doi: 10.1126/science.aaf4238
63.
YanJ, HorngT. Lipid metabolism in regulation of macrophage functions. Trends Cell Biol, 2020; 30(12):979–989; doi: 10.1016/j.tcb.2020.09.006
64.
StunaultMI, BoriesG, GuinamardRR, et al.Metabolism plays a key role during macrophage activation. Mediators Inflamm, 2018; 2018:2426138; doi: 10.1155/2018/2426138
65.
ChenL, TredgetE, WuP, et al.Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One, 2008; 3(4):e1886; doi: 10.1371/journal.pone.0001886
66.
MagginiJ, MirkinG, BognanniI, et al.Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One, 2010; 5(2):e9252; doi: 10.1371/journal.pone.0009252
67.
NémethK, LeelahavanichkulA, YuenP, et al.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 2009; 15(1):42–49; doi: 10.1038/nm.1905
68.
NakashimaT, HayashiM, TakayanagiH. New insights into osteoclastogenic signaling mechanisms. Trends Endocrinol Metab, 2012; 23(11):582–590; doi: 10.1016/j.tem.2012.05.005
69.
TakayanagiH. Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol, 2007; 7(4):292–304; doi: 10.1038/nri2062
70.
DengM, TanJ, HuC, et al.Modification of PLGA scaffold by MSC-derived extracellular matrix combats macrophage inflammation to initiate bone regeneration via TGF-β-induced protein. Adv Healthcare Mater, 2020; 9(13):e2000353; doi: 10.1002/adhm.202000353
71.
LiL, LiQ, GuiL, et al.Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis. Bioactive Mater, 2023; 19:24–37; doi: 10.1016/j.bioactmat.2022.03.037
72.
QiaoD, ChengS, XingZ, et al.Bio-inspired glycosylated nano-hydroxyapatites enhance endogenous bone regeneration by modulating macrophage M2 polarization. Acta Biomater, 2023; 162:135–148; doi: 10.1016/j.actbio.2023.03.027
73.
YanY, LuA, DouY, et al.Nanomedicines reprogram synovial macrophages by scavenging nitric oxide and silencing CA9 in progressive osteoarthritis. Adv Sci (Weinh), 2023; 10(11):e2207490; doi: 10.1002/advs.202207490
74.
LiB, XinZ, GaoS, et al.SIRT6-regulated macrophage efferocytosis epigenetically controls inflammation resolution of diabetic periodontitis. Theranostics, 2023; 13(1):231–249; doi: 10.7150/thno.78878
75.
SharifiaghdamM, ShaabaniE, Faridi-MajidiR, et al.Macrophages as a therapeutic target to promote diabetic wound healing. Mol Ther, 2022; 30(9):2891–2908; doi: 10.1016/j.ymthe.2022.07.016
76.
LiY, YangL, HouY, et al.Polydopamine-mediated graphene oxide and nanohydroxyapatite-incorporated conductive scaffold with an immunomodulatory ability accelerates periodontal bone regeneration in diabetes. Bioactive Mater, 2022; 18:213–227; doi: 10.1016/j.bioactmat.2022.03.021
77.
DaiX, HengBC, BaiY, et al.Restoration of electrical microenvironment enhances bone regeneration under diabetic conditions by modulating macrophage polarization. Bioact Mater, 2021; 6(7):2029–2038; doi: 10.1016/j.bioactmat.2020.12.020
78.
ToitaR, KangJ, TsuchiyaA. Phosphatidylserine liposome multilayers mediate the M1-to-M2 macrophage polarization to enhance bone tissue regeneration. Acta Biomater, 2022; 154:583–596; doi: 10.1016/j.actbio.2022.10.024
79.
WuM, ChenF, LiuH, et al.Bioinspired sandwich-like hybrid surface functionalized scaffold capable of regulating osteogenesis, angiogenesis, and osteoclastogenesis for robust bone regeneration. Mater Today Bio, 2022; 17:100458; doi: 10.1016/j.mtbio.2022.100458
80.
JiangF, QiX, WuX, et al.Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment. Bioactive Mater, 2023; 25:307–318; doi: 10.1016/j.bioactmat.2023.02.001
81.
JeppesenDK, FenixAM, FranklinJL, et al.Reassessment of exosome composition. Cell, 2019; 177(2):428–445.e18; doi: 10.1016/j.cell.2019.02.029
82.
DuanL, XuL, XuX, et al.Exosome-mediated delivery of gene vectors for gene therapy. Nanoscale, 2021; 13(3):1387–1397; doi: 10.1039/d0nr07622h
83.
LiangY, DuanL, LuJ, et al.Engineering exosomes for targeted drug delivery. Theranostics, 2021; 11(7):3183–3195; doi: 10.7150/thno.52570
84.
WeiF, LiM, CrawfordR, et al.Exosome-integrated titanium oxide nanotubes for targeted bone regeneration. Acta Biomater, 2019; 86:480–492; doi: 10.1016/j.actbio.2019.01.006
85.
WangD, LiuY, DiaoS, et al.Long non-coding RNAs within macrophage-derived exosomes promote bmsc osteogenesis in a bone fracture rat model. Int J Nanomed, 2023; 18:1063–1083; doi: 10.2147/ijn.S398446
86.
LiuY, YangZ, WangL, et al.Spatiotemporal immunomodulation using biomimetic scaffold promotes endochondral ossification-mediated bone healing. Adv Sci (Weinh), 2021; 8(11):e2100143; doi: 10.1002/advs.202100143
87.
DingT, KangW, LiJ, et al.An in situ tissue engineering scaffold with growth factors combining angiogenesis and osteoimmunomodulatory functions for advanced periodontal bone regeneration. J Nanobiotechnol, 2021; 19(1):247; doi: 10.1186/s12951-021-00992-4
88.
HuangD, XuK, HuangX, et al.Remotely temporal scheduled macrophage phenotypic transition enables optimized immunomodulatory bone regeneration. Small (Weinheim an der Bergstrasse, Germany), 2022; 18(39):e2203680; doi: 10.1002/smll.202203680
89.
XuZ, WuL, TangY, et al.Spatiotemporal regulation of the bone immune microenvironment via dam-like biphasic bionic periosteum for bone regeneration. Adv Healthcare Mater, 2023; 12(1):e2201661; doi: 10.1002/adhm.202201661
90.
XieX, WeiJ, ZhangB, et al.A self-assembled bilayer polypeptide-engineered hydrogel for spatiotemporal modulation of bactericidal and anti-inflammation process in osteomyelitis treatment. J Nanobiotechnol, 2022; 20(1):416; doi: 10.1186/s12951-022-01614-3
