The bone is an active tissue subjected to ongoing remodeling process regulated through a fine-tuned equilibrium between formation and resorption and is mainly regulated by osteoblasts, osteoclasts, and osteocytes. Recent developments have identified the essential importance of Osteal Macrophages (OsteoMacs), a unique subset of tissue-resident macrophages, in bone homeostasis. In contrast to osteoclasts, the mononuclear F4/80⁺ OsteoMacs are non-resorbing cells that promote osteoblast function, preserve the structure of the bone remodeling canopy, and regulate local immune responses of the skeletal microenvironment. This review was designed to summarize the uncovering, source, phenotypic characteristic as well as functional role of OsteoMacs in bone remodeling, osseointegration, and response to biomaterials. Knowledge of the cross talk between OsteoMacs and biomaterials provides new opportunities to improve bone regeneration via specific immunomodulation. OsteoMacs therefore, serve as a critical interface between the skeletal and immune systems; and have large relevance in implantology and regenerative medicine.
HumeDAMacDonaldKP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood2012; 119(8): 1810–1820. https://doi.org/10.1182/blood-2011-09-379214
4.
GordonSHumeDALoutitJF. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: macrophages of bone and associated connective tissue. J Cell Sci1984; 66: 189–194.
5.
ChangMKRaggattLJAlexanderKA, et al.Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol2008; 181(2): 1232–1244. https://doi.org/10.4049/jimmunol.181.2.1232
AndersenTLDelaisseJMSkorzynskaKE, et al.A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol2009; 174(1): 239–247. https://doi.org/10.2353/ajpath.2009.080627
9.
BolampertiSVillaIRubinacciA. Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Res2022; 10: 48. https://doi.org/10.1038/s41413-022-00219-8
BurnettSHKershenEJZhangJ, et al.Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. J Leukoc Biol2004; 75(4): 612–623. https://doi.org/10.1189/jlb.0903442
13.
WangJFanJYangX. Single cell RNA-seq analysis associates osm signaling in macrophages with osteogenic differentiation during heterotopic ossification. J Orthop Surg Res2025; 20(1): 1048. https://doi.org/10.1186/s13018-025-06435-2
14.
YangWWangYMoK, et al.Single-cell RNA sequencing reveals multiple immune cell subpopulations promote the formation of abnormal bone microenvironment in osteoporosis. Sci Rep2024; 14: 29493. https://doi.org/10.1038/s41598-024-80993-z
15.
HwangSJ. A mathematical modeling study on the role of osteal macrophages and osteocytes in bone remodeling. J Dent Hyg Sci2018; 18(2): 77–84.
16.
AlexanderKAChangMKMaylinER, et al.Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res2011; 26(7): 1517–1532. https://doi.org/10.1002/jbmr.354
17.
ChoSWSokiFNKohAJ, et al.Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proc Natl Acad Sci U S A2014; 111(4): 1545–1550. https://doi.org/10.1073/pnas.1315153111
18.
BatoonLMillardSMWullschlegerME, et al.CD169+ macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair. Biomater2017; 121: 86–102.
19.
MaQLZhaoLZLiuRR, et al.Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization. Biomater2014; 35(37): 9853–9867. https://doi.org/10.1016/j.biomaterials.2014.08.025
20.
HotchkissKMReddyGBHyzySL, et al.Titanium surface characteristics, including topography and wettability, alter macrophage activation. Acta Biomater2016; 31: 425–434. https://doi.org/10.1016/j.actbio.2015.12.003
21.
LeeCHKimYJJangJH, et al.Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces. Nanotechnology2016; 27(8): 085101. https://doi.org/10.1088/0957-4484/27/8/085101
22.
ZhangYChengXJansenJA, et al.Titanium surface characteristics modulate macrophage polarization. Mater Sci Eng C2019; 95: 143–151. https://doi.org/10.1016/j.msec.2018.10.065
23.
BahetiWChenXLaM, et al.Biomimetic HA-GO implant coating for enhanced osseointegration via macrophage M2 polarization-induced osteo-immunomodulation. J Appl Biomater Funct Mater2024; 22: 22808000241266665. https://doi.org/10.1177/22808000241266665
24.
YangRTalibHMironRJ, et al.OsteoMacs and their role in early implant failure and osseointegration. Comp Cont Educ Dent2022; 43(10): 586–592.
MuñozJAkhavanNSMullinsAP, et al.Macrophage polarization and osteoporosis: a review. Nutrients2020; 12(10): 2999. https://doi.org/10.3390/nu12102999
27.
MutrejaIYeZAparicioC. Cell responses to titanium and titanium alloys. In: MozafariM (ed) Handbook of biomaterials biocompatibility. Elsevier, 2020, pp. 423–452.
28.
BarbosaJNVasconcelosDP. Macrophage response to biomaterials. In: MozafariM (ed) Handbook of biomaterials biocompatibility. Elsevier, 2020, pp. 43–52.
SridharanRCameronARKellyDJ, et al.Biomaterial-based modulation of macrophage polarization: a review and suggested design principles. Mater Today2015; 18(6): 313–325. https://doi.org/10.1016/j.mattod.2015.01.019
32.
ChenZKleinTMurrayRZ, et al.Osteoimmunomodulation for the development of advanced bone biomaterials. Mater Today2016; 19(6): 304–321. https://doi.org/10.1016/j.mattod.2015.11.004
33.
HeYGaoYMaQ, et al.Nanotopographical cues for regulation of macrophages and osteoclasts: emerging opportunities for osseointegration. J Nanobiotechnol2022; 20(1): 36. https://doi.org/10.1186/s12951-022-01721-1
34.
XieYHuCFengY, et al.Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration. Regen Biomater2020; 7(3): 233–245. https://doi.org/10.1093/rb/rbaa006
35.
YiLTangRShaoC, et al.A biodegradable zinc alloy membrane with regulation of macrophage polarization for early vascularized bone regeneration. Biomater Res2025; 29: 0223. https://doi.org/10.34133/bmr.0223
36.
JensenPRAndersenTLChavassieuxP, et al.Bisphosphonates impair the onset of bone formation at remodeling sites. Bone2021; 145: 115850. https://doi.org/10.1016/j.bone.2021.115850
37.
LinYHChenCYChenKH, et al.Lithium-doped calcium silicate cement regulates the immune microenvironment and promotes M2 macrophage polarization for enhancing bone regeneration. J Biol Eng2025; 19(1): 3. https://doi.org/10.1186/s13036-024-00467-8
38.
LiYXieXDingC, et al.Immunomodulatory biomaterials for bone and soft tissue chronic inflammation diseases. Small Sci2025; 5(12): e202500260. https://doi.org/10.1002/smsc.202500260
39.
SpillerKLNassiriSWitherelCE, et al.Sequential delivery of immunomodulatory cytokines from biomaterials to promote macrophage polarization and enhance tissue regeneration. Biomater2015; 37: 194–207. https://doi.org/10.1016/j.biomaterials.2014.10.017
40.
ChenYWuXLiJ, et al.Bone-targeted nanoparticle drug delivery system: an emerging strategy for bone-related disease. Front Pharmacol2022; 13: 909408. https://doi.org/10.3389/fphar.2022.909408
