Current Osteoporosis Reports

, Volume 15, Issue 4, pp 385–395 | Cite as

Osteomacs and Bone Regeneration

  • Lena Batoon
  • Susan Marie Millard
  • Liza Jane Raggatt
  • Allison Robyn PettitEmail author
Osteoimmunology (MB Humphrey and M Nakamura, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Osteoimmunology


Purpose of Review

Mounting evidence supporting the critical contribution of macrophages, in particular osteal macrophages, to bone regeneration is reviewed. We specifically examine the potential role of macrophages in the basic multicellular units coordinating lifelong bone regeneration via remodelling and bone regeneration in response to injury. We review and discuss the distinctions between macrophage and osteoclast contributions to bone homeostasis, particularly the dichotomous role of the colony-stimulating factor 1—colony-stimulating factor 1 receptor axis.

Recent Findings

The impact of inflammation associated with aging and other hallmarks of aging, including senescence, on macrophage function is addressed in the context of osteoporosis and delayed fracture repair. Resident macrophages versus recruited macrophage contributions to fracture healing are also discussed.


We identify some of the remaining knowledge gaps that will need to be closed in order to maximise benefits from therapeutically modulating or mimicking the function of macrophages to improve bone health and regeneration over a lifetime.


Macrophages Bone regeneration Fracture repair Senescence Inflammaging Osteoporosis 



This work was supported by the Mater Foundation and an Australian and New Zealand Bone and Mineral Society Gap Fellowship to ARP.

Dr. Andy C. Wu contributed to experiments in Fig. 1.

Compliance with Ethical Standards

Conflict of Interest

Lena Batoon, Allison Pettit, Liza Jane Raggatt and Susan Millard declare no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors comply with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards and international/national/institutional guidelines). Animal experiments were approved by The University of Queensland Health Sciences Ethics Committee and performed in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.


Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. 1.
    Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep. 2014;3:481.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Karasik D, Rivadeneira F, Johnson ML. The genetics of bone mass and susceptibility to bone diseases. Nat Rev Rheumatol. 2016;12(8):496.PubMedGoogle Scholar
  3. 3.
    Samaras N, Papadopoulou MA, Samaras D, Ongaro F. Off-label use of hormones as an antiaging strategy: a review. Clin Interv Aging. 2014;9:1175–86.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Palermo A, D'Onofrio L, Buzzetti R, Manfrini S, Napoli N. Pathophysiology of bone fragility in patients with diabetes. Calcif Tissue Int. 2017;100(2):122–32.PubMedGoogle Scholar
  5. 5.
    Kazama JJ. Chronic kidney disease and fragility fracture. Clin Exp Nephrol. 2017;21(Suppl 1):46–52.PubMedGoogle Scholar
  6. 6.
    Hernlund E, Svedbom A, Ivergard M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos. 2013;8(1–2):136. 1-115 PubMedPubMedCentralGoogle Scholar
  7. 7.
    Darba J, Kaskens L, Perez-Alvarez N, Palacios S, Neyro JL, Rejas J. Disability-adjusted-life-years losses in postmenopausal women with osteoporosis: a burden of illness study. BMC Public Health. 2015;15:324.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Center JR. Fracture burden: what two and a half decades of Dubbo Osteoporosis Epidemiology Study data reveal about clinical outcomes of osteoporosis. Curr Osteoporos Rep. 2017;15(2):88–95 doi: 10.1007/s11914-017-0352-5 PubMedGoogle Scholar
  9. 9.
    Drake MT, Clarke BL, Lewiecki EM. The pathophysiology and treatment of osteoporosis. Clin Therapeut. 2015;37(8):1837–50.Google Scholar
  10. 10.
    Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551–5.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Julier Z, Park AJ, Briquez PS, Martino MM. Promoting tissue regeneration by modulating the immune system. Acta Biomater. 2017.Google Scholar
  12. 12.
    Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol. 2008;19(5):459–66.Google Scholar
  13. 13.
    Santolini E, West R, Giannoudis PV. Risk factors for long bone fracture non-union: a stratification approach based on the level of the existing scientific evidence. Injury. 2015;46(Suppl 8):S8–S19.PubMedGoogle Scholar
  14. 14.
    Foulke BA, Kendal AR, Murray DW, Pandit H. Fracture healing in the elderly: a review. Maturitas. 2016;92:49–55.PubMedGoogle Scholar
  15. 15.
    Dong L, Wang C. Harnessing the power of macrophages/monocytes for enhanced bone tissue engineering. Trends Biotechnol. 2013;31(6):342–6.PubMedGoogle Scholar
  16. 16.
    Kim YH, Furuya H, Tabata Y. Enhancement of bone regeneration by dual release of a macrophage recruitment agent and platelet-rich plasma from gelatin hydrogels. Biomaterials. 2014;35(1):214–24.PubMedGoogle Scholar
  17. 17.
    Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20(8):857–69.PubMedGoogle Scholar
  18. 18.
    Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41(1):21–35.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kaur S, Raggatt LJ, Batoon L, Hume DA, Levesque JP, Pettit AR. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches. Semin Cell Dev Biol. 2017;61:12–21.PubMedGoogle Scholar
  20. 20.
    Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, et al. 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(2):1232–44.PubMedGoogle Scholar
  21. 21.
    Alexander KA, Raggatt LJ, Millard S, Batoon L, Chiu-Ku Wu A, Chang MK, et al. Resting and injury-induced inflamed periosteum contain multiple macrophage subsets that are located at sites of bone growth and regeneration. Immunol Cell Biol. 2017;95(1):7–16.PubMedGoogle Scholar
  22. 22.
    •• Cho SW, Soki FN, Koh AJ, Eber MR, Entezami P, Park SI, et al. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proc Natl Acad Sci U S A. 2014;111(4):1545–50. First report that macrophages influence the anabolic actions of parathyroid hormone. PubMedPubMedCentralGoogle Scholar
  23. 23.
    Wu AC, Raggatt LJ, Alexander KA, Pettit AR. Unraveling macrophage contributions to bone repair. Bonekey Rep. 2013;2Google Scholar
  24. 24.
    Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res. 2007;22(8):1197–207.PubMedGoogle Scholar
  25. 25.
    Nicolaidou V, Wong MM, Redpath AN, Ersek A, Baban DF, Williams LM, et al. Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation. PLoS One. 2012;7(7):e39871.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J, et al. Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells. 2012;30(4):762–72.PubMedGoogle Scholar
  27. 27.
    Adutler-Lieber S, Ben-Mordechai T, Naftali-Shani N, Asher E, Loberman D, Raanani E, et al. Human macrophage regulation via interaction with cardiac adipose tissue-derived mesenchymal stromal cells. J Cardiovasc Pharmacol Ther. 2013;18(1):78–86.PubMedGoogle Scholar
  28. 28.
    Pirraco RP, Reis RL, Marques AP. Effect of monocytes/macrophages on the early osteogenic differentiation of hBMSCs. J Tissue Eng Regen Med. 2013;7(5):392–400.PubMedGoogle Scholar
  29. 29.
    Fernandes TJ, Hodge JM, Singh PP, Eeles DG, Collier FM, Holten I, et al. Cord blood-derived macrophage-lineage cells rapidly stimulate osteoblastic maturation in mesenchymal stem cells in a glycoprotein-130 dependent manner. PLoS One. 2013;8(9):e73266.PubMedPubMedCentralGoogle Scholar
  30. 30.
    • Vi L, Baht GS, Whetstone H, Ng A, Wei Q, Poon R, et al. Macrophages promote osteoblastic differentiation in-vivo: implications in fracture repair and bone homeostasis. J Bone Miner Res. 2014;30(6):1090–102. Data reporting the involvement of macrophages in skeletal growth and conformation of earlier reports that they are necessary in bone repair. Google Scholar
  31. 31.
    Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116(23):4815–28.PubMedGoogle Scholar
  32. 32.
    Alexander KA, Chang MK, Maylin ER, Kohler T, Muller R, Wu AC, et al. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res. 2011;26(7):1517–32.PubMedGoogle Scholar
  33. 33.
    • Raggatt LJ, Wullschleger ME, Alexander KA, Wu AC, Millard SM, Kaur S, et al. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am J Pathol. 2014;184(12):3192–204. Comprehensive assessment of macrophage dynamics during endochondral fracture healing and definitive proof that macrophages are essential for bone repair. PubMedGoogle Scholar
  34. 34.
    •• Guihard P, Boutet MA, Brounais-Le Royer B, Gamblin AL, Amiaud J, Renaud A, et al. Oncostatin m, an inflammatory cytokine produced by macrophages, supports intramembranous bone healing in a mouse model of tibia injury. Am J Pathol. 2015;185(3):765–75. Use of genetically modified mice to show that oncostatin M is an anabolic signal directing intramembranous bone healing. PubMedGoogle Scholar
  35. 35.
    Abram CL, Roberge GL, Hu Y, Lowell CA. Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J Immunol Methods. 2014;408:89–100.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Mise-Omata S, Alles N, Fukazawa T, Aoki K, Ohya K, Jimi E, et al. NF-kappaB RELA-deficient bone marrow macrophages fail to support bone formation and to maintain the hematopoietic niche after lethal irradiation and stem cell transplantation. Int Immunol. 2014;26(11):607–18.PubMedGoogle Scholar
  37. 37.
    Chang KH, Sengupta A, Nayak RC, Duran A, Lee SJ, Pratt RG, et al. p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-kappaB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche. Cell Rep. 2014;9(6):2084–97.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Jenkins SJ, Hume DA. Homeostasis in the mononuclear phagocyte system. Trends Immunol. 2014;35(8):358–67.PubMedGoogle Scholar
  39. 39.
    Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, et al. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 2009;10(11):R130.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, Ravasi T. The mononuclear phagocyte system revisited. J Leukoc Biol. 2002;72(4):621–7.PubMedGoogle Scholar
  41. 41.
    Michalski MN, McCauley LK. Macrophages and skeletal health. Pharmacol Ther. 2017;S0163-7258(17):30031-1. doi: 10.1016/j.pharmthera.CrossRefGoogle Scholar
  42. 42.
    Hayman AR. Tartrate-resistant acid phosphatase (TRAP) and the osteoclast/immune cell dichotomy. Autoimmunity. 2008;41(3):218–23.PubMedGoogle Scholar
  43. 43.
    Sinder BP, Pettit AR, McCauley LK. Macrophages: their emerging roles in bone. J Bone Miner Res. 2015;30(12):2140–9.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Li YP, Chen W. Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression. J Bone Miner Res. 1999;14(4):487–99.PubMedGoogle Scholar
  45. 45.
    Lee SK, Goldring SR, Lorenzo JA. Expression of the calcitonin receptor in bone marrow cell cultures and in bone: a specific marker of the differentiated osteoclast that is regulated by calcitonin. Endocrinology. 1995;136(10):4572–81.PubMedGoogle Scholar
  46. 46.
    Hou WS, Li W, Keyszer G, Weber E, Levy R, Klein MJ, et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 2002;46(3):663–74.PubMedGoogle Scholar
  47. 47.
    •• Kang JH, Sim JS, Zheng T, Yim M. F4/80 inhibits osteoclast differentiation via downregulation of nuclear factor of activated T cells, cytoplasmic 1. Arch Pharm Res. 2017. This study reports bone marrow macrophages with high F4/80 expression have low NFATc1 expression and poor osteoclastogenetic capacity, suggesting F4/80 expression suppresses RANKL-induced osteoclastogenetic potential.Google Scholar
  48. 48.
    Mizoguchi T, Muto A, Udagawa N, Arai A, Yamashita T, Hosoya A, et al. Identification of cell cycle-arrested quiescent osteoclast precursors in vivo. J Cell Biol. 2009;184(4):541–54.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23.Google Scholar
  50. 50.
    Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159(5):1689–99.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Wu AC, He Y, Broomfield A, Paatan NJ, Harrington BS, Tseng HW, et al. CD169(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer. J Pathol. 2016;239(2):218–30.PubMedGoogle Scholar
  52. 52.
    Lawson MA, McDonald MM, Kovacic N, Hua Khoo W, Terry RL, Down J, et al. Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun. 2015;6:8983.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford). 2006.Google Scholar
  54. 54.
    Michalski MN, Koh AJ, Weidner S, Roca H, McCauley LK. Modulation of osteoblastic cell efferocytosis by bone marrow macrophages. J Cell Biochem. 2016;117(12):2697–706.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Everts V, Delaisse JM, Korper W, Jansen DC, Tigchelaar-Gutter W, Saftig P, et al. The bone lining cell: its role in cleaning Howship’s lacunae and initiating bone formation. J Bone Miner Res. 2002;17(1):77–90.PubMedGoogle Scholar
  56. 56.
    Tran Van P, Vignery A, Baron R. An electron-microscopic study of the bone-remodeling sequence in the rat. Cell Tissue Res. 1982;225(2):283–92.PubMedGoogle Scholar
  57. 57.
    Takahashi T, Kurihara N, Takahashi K, Kumegawa M. An ultrastructural study of phagocytosis in bone by osteoblastic cells from fetal mouse calvaria in vitro. Arch Oral Biol. 1986;31(10):703–6.PubMedGoogle Scholar
  58. 58.
    Rifkin BR, Heijl L. The occurrence of mononuclear cells at sites of osteoclastic bone resorption in experimental periodontitis. J Periodontol. 1979;50(12):636–40.PubMedGoogle Scholar
  59. 59.
    Loi F, Cordova LA, Pajarinen J, Lin TH, Yao Z, Goodman SB. Inflammation, fracture and bone repair. Bone. 2016;86:119–30.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Huber-Lang M, Kovtun A, Ignatius A. The role of complement in trauma and fracture healing. Semin Immunol. 2013;25(1):73–8.PubMedGoogle Scholar
  61. 61.
    Andrew JG, Andrew SM, Freemont AJ, Marsh DR. Inflammatory cells in normal human fracture healing. Acta Orthop Scand. 1994;65(4):462–6.PubMedGoogle Scholar
  62. 62.
    Hankemeier S, Grassel S, Plenz G, Spiegel HU, Bruckner P, Probst A. Alteration of fracture stability influences chondrogenesis, osteogenesis and immigration of macrophages. J Orthop Res. 2001;19(4):531–8.PubMedGoogle Scholar
  63. 63.
    Xing Z, Lu C, Hu D, Yu YY, Wang X, Colnot C, et al. Multiple roles for CCR2 during fracture healing. Dis Model Mech. 2010;3(7–8):451–8.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Abou-Khalil R, Yang F, Mortreux M, Lieu S, Yu YY, Wurmser M, et al. Delayed bone regeneration is linked to chronic inflammation in murine muscular dystrophy. J Bone Miner Res. 2014;29(2):304–15.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Kawao N, Tamura Y, Horiuchi Y, Okumoto K, Yano M, Okada K, et al. The tissue fibrinolytic system contributes to the induction of macrophage function and CCL3 during bone repair in mice. PLoS One. 2015;10(4):e0123982.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Schlundt C, El Khassawna T, Serra A, Dienelt A, Wendler S, Schell H, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone. 2015; doi: 10.1016/j.bone.2015.10.019.PubMedGoogle Scholar
  67. 67.
    Sarahrudi K, Mousavi M, Grossschmidt K, Sela N, Konig F, Vecsei V, et al. The impact of colony-stimulating factor-1 on fracture healing: an experimental study. J Orthop Res. 2009;27(1):36–41.PubMedGoogle Scholar
  68. 68.
    Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A. 2003;100(18):10405–10.PubMedPubMedCentralGoogle Scholar
  69. 69.
    McLean RR. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep. 2009;7(4):134–9.PubMedGoogle Scholar
  70. 70.
    Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab. 2017;28(3):199–212.PubMedGoogle Scholar
  71. 71.
    Dimitrijevic M, Stanojevic S, Blagojevic V, Curuvija I, Vujnovic I, Petrovic R, et al. Aging affects the responsiveness of rat peritoneal macrophages to GM-CSF and IL-4. Biogerontology. 2016;17(2):359–71.PubMedGoogle Scholar
  72. 72.
    Stranks AJ, Hansen AL, Panse I, Mortensen M, Ferguson DJ, Puleston DJ, et al. Autophagy controls acquisition of aging features in macrophages. J Innate Immun. 2015;7(4):375–91.PubMedGoogle Scholar
  73. 73.
    Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther. 2016;7:44.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Abdelmagid SM, Barbe MF, Safadi FF. Role of inflammation in the aging bones. Life Sci. 2015;123:25–34.PubMedGoogle Scholar
  75. 75.
    •• Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 2016;31(11):1920–9. This study shows that with aging in mice B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes become senescent, and that osteocytes and myeloid cells develop a senescence-associated secretory phenotype . PubMedPubMedCentralGoogle Scholar
  76. 76.
    Gibon E, Loi F, Cordova LA, Pajarinen J, Lin T, Lu L, et al. Aging affects bone marrow macrophage polarization: relevance to bone healing. Regenerative Eng Transl Med. 2016;2(2):98–104.Google Scholar
  77. 77.
    Sagiv A, Krizhanovsky V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology. 2013;14(6):617–28.PubMedGoogle Scholar
  78. 78.
    •• Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging. 2016;8(7):1294–315. This paper describes a non-senescent population of macrophages with a senescent phenotype that needs to be considered when evaluation senescent cells in aging . PubMedPubMedCentralGoogle Scholar
  79. 79.
    Onal M, Piemontese M, Xiong J, Wang Y, Han L, Ye S, et al. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem. 2013;288(24):17432–40.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Yang Y, Zheng X, Li B, Jiang S, Jiang L. Increased activity of osteocyte autophagy in ovariectomized rats and its correlation with oxidative stress status and bone loss. Biochem Biophys Res Commun. 2014;451(1):86–92.PubMedGoogle Scholar
  81. 81.
    Camuzard O, Santucci-Darmanin S, Breuil V, Cros C, Gritsaenko T, Pagnotta S, et al. Sex-specific autophagy modulation in osteoblastic lineage: a critical function to counteract bone loss in female. Oncotarget. 2016;7(41):66416–28.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Lopas LA, Belkin NS, Mutyaba PL, Gray CF, Hankenson KD, Ahn J. Fractures in geriatric mice show decreased callus expansion and bone volume. Clin Orthop Relat Res. 2014;472(11):3523–32.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Nikolaou VS, Efstathopoulos N, Kontakis G, Kanakaris NK, Giannoudis PV. The influence of osteoporosis in femoral fracture healing time. Injury. 2009;40(6):663–8.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Cortet B. Bone repair in osteoporotic bone: postmenopausal and cortisone-induced osteoporosis. Osteoporos Int. 2011;22(6):2007–10.PubMedGoogle Scholar
  85. 85.
    Pang J, Ye M, Gu X, Cao Y, Zheng Y, Guo H, et al. Ovariectomy-induced osteopenia influences the middle and late periods of bone healing in a mouse femoral osteotomy model. Rejuvenation Res. 2015;18(4):356–65.PubMedGoogle Scholar
  86. 86.
    Mathew G, Hanson BP. Global burden of trauma: need for effective fracture therapies. Indian J Orthop. 2009;43(2):111–6.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Slade Shantz JA, Yu YY, Andres W, Miclau T 3rd, Marcucio R. Modulation of macrophage activity during fracture repair has differential effects in young adult and elderly mice. J Orthop Trauma. 2014;28(Suppl 1):S10-4.PubMedGoogle Scholar
  88. 88.
    Schmidt-Bleek K, Schell H, Schulz N, Hoff P, Perka C, Buttgereit F, et al. Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res. 2012;347(3):567–73.PubMedGoogle Scholar
  89. 89.
    Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8(3):133–43.Google Scholar
  90. 90.
    Kim KA, Jeong JJ, Yoo SY, Kim DH. Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice. BMC Microbiol. 2016;16:9.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Behrends DA, Hui D, Gao C, Awlia A, Al-Saran Y, Li A, et al. Defective bone repair in C57Bl6 mice with acute systemic inflammation. Clin Orthop Relat Res. 2017;475(3):906–16.PubMedGoogle Scholar
  92. 92.
    Hume DA. The many alternative faces of macrophage activation. Front Immunol. 2015;6:370.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Xing Z, Lu C, Hu D, Miclau T 3rd, Marcucio RS. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice. J Orthop Res. 2010;28(8):1000–6.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Baht GS, Silkstone D, Vi L, Nadesan P, Amani Y, Whetstone H, et al. Exposure to a youthful circulation rejuvenates bone repair through modulation of beta-catenin. Nat Commun. 2015;6:7131.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32.PubMedGoogle Scholar
  96. 96.
    Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 2012;119(8):1810–20.PubMedGoogle Scholar
  97. 97.
    Stutchfield BM, Antoine DJ, Mackinnon AC, Gow DJ, Bain CC, Hawley CA, et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology. 2015;149(7):1896–909. e14 PubMedPubMedCentralGoogle Scholar
  98. 98.
    Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol. 2015;22:41–50.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Dewar AL, Farrugia AN, Condina MR, Bik To L, Hughes TP, Vernon-Roberts B, et al. Imatinib as a potential antiresorptive therapy for bone disease. Blood. 2006;107(11):4334–7.PubMedGoogle Scholar
  100. 100.
    Haegel H, Thioudellet C, Hallet R, Geist M, Menguy T, Le Pogam F, et al. A unique anti-CD115 monoclonal antibody which inhibits osteolysis and skews human monocyte differentiation from M2-polarized macrophages toward dendritic cells. MAbs. 2013;5(5):736–47.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, et al. Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts. PLoS One. 2013;8(9):e73310.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Sauter KA, Pridans C, Sehgal A, Bain CC, Scott C, Moffat L, et al. The MacBlue binary transgene (csf1r-gal4VP16/UAS-ECFP) provides a novel marker for visualisation of subsets of monocytes, macrophages and dendritic cells and responsiveness to CSF1 administration. PLoS One. 2014;9(8):e105429.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Cenci S, Weitzmann MN, Gentile MA, Aisa MC, Pacifici R. M-CSF neutralization and egr-1 deficiency prevent ovariectomy-induced bone loss. J Clin Invest. 2000;105(9):1279–87.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Lloyd SA, Yuan YY, Simske SJ, Riffle SE, Ferguson VL, Bateman TA. Administration of high-dose macrophage colony-stimulating factor increases bone turnover and trabecular volume fraction. J Bone Miner Metab. 2009;27(5):546–54.PubMedGoogle Scholar
  105. 105.
    Garceau V, Balic A, Garcia-Morales C, Sauter KA, McGrew MJ, Smith J, et al. The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor receptor. BMC Biol. 2015;13:12.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120(3):613–25.PubMedGoogle Scholar
  107. 107.
    Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450–62.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Kuziel WA, Morgan SJ, Dawson TC, Griffin S, Smithies O, Ley K, et al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A. 1997;94(22):12053–8.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Tsou CL, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007;117(4):902–9.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Alexander KA, Flynn R, Lineburg KE, Kuns RD, Teal BE, Olver SD, et al. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest. 2014;124(10):4266–80.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Mader TL, Novotny SA, Lin AS, Guldberg RE, Lowe DA, Warren GL. CCR2 elimination in mice results in larger and stronger tibial bones but bone loss is not attenuated following ovariectomy or muscle denervation. Calcif Tissue Int. 2014;95(5):457–66.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Ishikawa M, Ito H, Kitaori T, Murata K, Shibuya H, Furu M, et al. MCP/CCR2 signaling is essential for recruitment of mesenchymal progenitor cells during the early phase of fracture healing. PLoS One. 2014;9(8):e104954.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Chan JK, Glass GE, Ersek A, Freidin A, Williams GA, Gowers K, et al. Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. EMBO Mol Med. 2015;7(5):547–61.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Muller PA, Koscso B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell. 2014;158(2):300–13.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Lena Batoon
    • 1
  • Susan Marie Millard
    • 1
  • Liza Jane Raggatt
    • 1
    • 2
  • Allison Robyn Pettit
    • 1
    • 2
    Email author
  1. 1.Bones and Immunology Laboratory, Cancer Biology and Care ProgramMater Research Institute - The University of Queensland, Translational Research InstituteWoolloongabbaAustralia
  2. 2.Faculty of MedicineThe University of QueenslandHerstonAustralia

Personalised recommendations