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Current Osteoporosis Reports

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01-08-2017 | Osteoimmunology (M Humphrey and M Nakamura, Section Editors)

Osteoimmunology in Bone Fracture Healing

Authors: Takehito Ono, Hiroshi Takayanagi

Published in: Current Osteoporosis Reports | Issue 4/2017

Abstract

Purpose of Review

In the process of bone fracture healing, inflammation is thought to be an essential process that precedes bone formation and remodeling. We review recent studies on bone fracture healing from an osteoimmunological point of view.

Recent Findings

Based on previous observations that many types of immune cells infiltrate into the bone injury site and release a variety of molecules, recent studies have addressed the roles of specific immune cell subsets. Macrophages and interleukin (IL)-17-producing γδ T cells enhance bone healing, whereas CD8⁺ T cells impair bone repair. Additionally, IL-10-producing B cells may contribute to bone healing by suppressing excessive and/or prolonged inflammation. Although the involvement of other cells and molecules has been suggested, the precise underlying mechanisms remain elusive.

Summary

Accumulating evidence has begun to reveal the deeper picture of bone fracture healing. Further studies are required for the development of novel therapeutic strategies for bone fracture.

Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol. 2009;5(12):667–76.PubMedCrossRef

Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015;15(1):30–44.PubMedPubMedCentralCrossRef

Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol. 2016;49:30–6.PubMedCrossRef

Komatsu N, Takayanagi H. Inflammation and bone destruction in arthritis: synergistic activity of immune and mesenchymal cells in joints. Front Immunol. 2012;3:77.PubMedPubMedCentralCrossRef

Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat + CD3 + CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.PubMedCrossRef

•• Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11(1):45–54. A comprehensive review of bone fracture healing.PubMedCrossRef

Bissinger O, Kreutzer K, Gotz C, Hapfelmeier A, Pautke C, Vogt S, et al. A biomechanical, micro-computertomographic and histological analysis of the influence of diclofenac and prednisolone on fracture healing in vivo. BMC Musculoskelet Disord. 2016;17(1):383.PubMedPubMedCentralCrossRef

Holstein JH, Klein M, Garcia P, Histing T, Culemann U, Pizanis A, et al. Rapamycin affects early fracture healing in mice. Br J Pharmacol. 2008;154(5):1055–62.PubMedPubMedCentralCrossRef

Satoh K, Mark H, Zachrisson P, Rydevik B, Byrod G, Kikuchi S, et al. Effect of methotrexate on fracture healing. Fukushima J Med Sci. 2011;57(1):11–8.PubMedCrossRef

10.

Richardson J, Hill AM, Johnston CJ, McGregor A, Norrish AR, Eastwood D, et al. Fracture healing in HIV-positive populations. J Bone Joint Surg (Br). 2008;90(8):988–94.CrossRef

11.

Histing T, Garcia P, Matthys R, Leidinger M, Holstein JH, Kristen A, et al. An internal locking plate to study intramembranous bone healing in a mouse femur fracture model. J Orthop Res. 2010;28(3):397–402.PubMedCrossRef

12.

Monfoulet L, Rabier B, Chassande O, Fricain JC. Drilled hole defects in mouse femur as models of intramembranous cortical and cancellous bone regeneration. Calcif Tissue Int. 2010;86(1):72–81.PubMedCrossRef

13.

Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78(1):71–100.PubMedPubMedCentral

14.

Vannella KM, Wynn TA. Mechanisms of organ injury and repair by macrophages. Annu Rev Physiol. 2017;79:593–617.PubMedCrossRef

15.

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.PubMedPubMedCentralCrossRef

16.

Wu AC, Raggatt LJ, Alexander KA, Pettit AR. Unraveling macrophage contributions to bone repair. Bonekey Rep. 2013;2:373.PubMedPubMedCentralCrossRef

17.

• 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. This study demonstrated for the first time that macrophages play a crucial role in bone fracture healing by promoting bone formation.PubMedCrossRef

18.

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.

19.

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. 2015;30(6):1090–102.PubMedCrossRef

20.

Bosselut R. CD4/CD8-lineage differentiation in the thymus: from nuclear effectors to membrane signals. Nat Rev Immunol. 2004;4(7):529–40.PubMedCrossRef

21.

Kitagawa Y, Ohkura N, Sakaguchi S. Molecular determinants of regulatory T cell development: the essential roles of epigenetic changes. Front Immunol. 2013;4:106.PubMedPubMedCentralCrossRef

22.

Ciofani M, Zuniga-Pflucker JC. Determining γδ versus αβ T cell development. Nat Rev Immunol. 2010;10(9):657–63.PubMedCrossRef

23.

Vantourout P, Hayday A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat Rev Immunol. 2013;13(2):88–100.PubMedPubMedCentralCrossRef

24.

Bonneville M, O'Brien RL, Born WK. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol. 2010;10(7):467–78.PubMedCrossRef

25.

Konnecke I, Serra A, El Khassawna T, Schlundt C, Schell H, Hauser A, et al. T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone. 2014;64:155–65.PubMedCrossRef

26.

• Toben D, Schroeder I, El Khassawna T, Mehta M, Hoffmann JE, Frisch JT, et al. Fracture healing is accelerated in the absence of the adaptive immune system. J Bone Miner Res. 2011;26(1):113–24. Study demonstrated the suppressive function of lymphocytes on bone fracture healing.PubMedCrossRef

27.

• Nam D, Mau E, Wang Y, Wright D, Silkstone D, Whetstone H, et al. T-lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair. PLoS One. 2012;7(6):e40044. This study highlighted another aspect of lymphocytes as an enhancer of bone fracture healing.PubMedPubMedCentralCrossRef

28.

• Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, et al. Terminally differentiated CD8(+) T cells negatively affect bone regeneration in humans. Sci Transl Med. 2013;5(177):177ra36. Study addressed the function of a specific T cell subset in bone fracture healing for the first time and demonstrated that CD8+ T cells suppress bone fracture healing.PubMedCrossRef

29.

•• Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, et al. IL-17-producing γδ T cells enhance bone regeneration. Nat Commun. 2016;7:10928. This study revealed that the γδ T cell produces IL-17A to promote bone formation in the bone fracture healing process, providing a novel role for γδ T cell in bone metabolism.PubMedPubMedCentralCrossRef

30.

Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31(2):321–30.PubMedCrossRef

31.

Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31(2):331–41.PubMedCrossRef

32.

Han G, Geng S, Li Y, Chen G, Wang R, Li X, et al. γδ T-cell function in sepsis is modulated by C5a receptor signalling. Immunology. 2011;133(3):340–9.PubMedPubMedCentralCrossRef

33.

Akitsu A, Ishigame H, Kakuta S, Chung SH, Ikeda S, Shimizu K, et al. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells. Nat Commun. 2015;6:7464.PubMedCrossRef

34.

Lanca T, Costa MF, Goncalves-Sousa N, Rei M, Grosso AR, Penido C, et al. Protective role of the inflammatory CCR2/CCL2 chemokine pathway through recruitment of type 1 cytotoxic γδ T lymphocytes to tumor beds. J Immunol. 2013;190(12):6673–80.PubMedCrossRef

35.

Penido C, Costa MF, Souza MC, Costa KA, Candea AL, Benjamim CF, et al. Involvement of CC chemokines in gammadelta T lymphocyte trafficking during allergic inflammation: the role of CCL2/CCR2 pathway. Int Immunol. 2008;20(1):129–39.PubMedCrossRef

36.

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.PubMedPubMedCentralCrossRef

37.

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.PubMedPubMedCentralCrossRef

38.

Shen P, Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol. 2015;15(7):441–51.PubMedCrossRef

39.

Yang S, Ding W, Feng D, Gong H, Zhu D, Chen B, et al. Loss of B cell regulatory function is associated with delayed healing in patients with tibia fracture. APMIS. 2015;123(11):975–85.PubMedCrossRef

40.

Raggatt LJ, Alexander KA, Kaur S, Wu AC, MacDonald KP, Pettit AR. Absence of B cells does not compromise intramembranous bone formation during healing in a tibial injury model. Am J Pathol. 2013;182(5):1501–8.PubMedCrossRef

41.

Sun G, Wang Y, Ti Y, Wang J, Zhao J, Qian H. Regulatory B cell is critical in bone union process through suppressing proinflammatory cytokines and stimulating Foxp3 in Treg cells. Clin Exp Pharmacol Physiol. 2016.

42.

Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 2006;54(1):158–68.PubMedCrossRef

43.

Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A. 1993;90(24):11924–8.PubMedPubMedCentralCrossRef

44.

Kleber C, Becker CA, Malysch T, Reinhold JM, Tsitsilonis S, Duda GN, et al. Temporal profile of inflammatory response to fracture and hemorrhagic shock: proposal of a novel long-term survival murine multiple trauma model. J Orthop Res. 2015;33(7):965–70.PubMedCrossRef

45.

Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Pleshko Camacho N, Bostrom MP. Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone. 2007;41(6):928–36.PubMedPubMedCentralCrossRef

46.

Wallace A, Cooney TE, Englund R, Lubahn JD. Effects of interleukin-6 ablation on fracture healing in mice. J Orthop Res. 2011;29(9):1437–42.PubMedCrossRef

47.

Sonomoto K, Yamaoka K, Oshita K, Fukuyo S, Zhang X, Nakano K, et al. Interleukin-1beta induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathway. Arthritis Rheum. 2012;64(10):3355–63.PubMedCrossRef

48.

• Glass GE, Chan JK, Freidin A, Feldmann M, Horwood NJ, Nanchahal J. TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells. Proc Natl Acad Sci U S A. 2011;108(4):1585–90. This study provided evidence for the promotive effects of TNF-α on bone fracture healing by enhancing mesenchymal cell migration and bone formation.PubMedPubMedCentralCrossRef

49.

Bellido T, Borba VZ, Roberson P, Manolagas SC. Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation. Endocrinology. 1997;138(9):3666–76.PubMedCrossRef

50.

Bluml S, Scheinecker C, Smolen JS, Redlich K. Targeting TNF receptors in rheumatoid arthritis. Int Immunol. 2012;24(5):275–81.PubMedCrossRef

51.

Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991;10(13):4025–31.PubMedPubMedCentralCrossRef

52.

Horai R, Nakajima A, Habiro K, Kotani M, Nakae S, Matsuki T, et al. TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J Clin Invest. 2004;114(11):1603–11.PubMedPubMedCentralCrossRef

53.

Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13(2):156–63.PubMedCrossRef

54.

Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Tsay A, Fitch J, et al. Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res. 2003;18(9):1584–92.PubMedCrossRef

55.

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.PubMedPubMedCentralCrossRef

56.

Hess K, Ushmorov A, Fiedler J, Brenner RE, Wirth T. TNFalpha promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-kappaB signaling pathway. Bone. 2009;45(2):367–76.PubMedCrossRef

57.

Ding J, Ghali O, Lencel P, Broux O, Chauveau C, Devedjian JC, et al. TNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. Life Sci. 2009;84(15-16):499–504.PubMedCrossRef

58.

Gilbert LC, Rubin J, Nanes MS. The p55 TNF receptor mediates TNF inhibition of osteoblast differentiation independently of apoptosis. Am J Physiol Endocrinol Metab. 2005;288(5):E1011–8.PubMedCrossRef

59.

Lacey DC, Simmons PJ, Graves SE, Hamilton JA. Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation. Osteoarth Cartil. 2009;17(6):735–42.CrossRef

60.

Sang C, Zhang Y, Chen F, Huang P, Qi J, Wang P, et al. Tumor necrosis factor alpha suppresses osteogenic differentiation of MSCs by inhibiting semaphorin 3B via Wnt/beta-catenin signaling in estrogen-deficiency induced osteoporosis. Bone. 2016;84:78–87.PubMedCrossRef

61.

Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30(1):108–19.PubMedCrossRef

62.

Yu JJ, Ruddy MJ, Wong GC, Sfintescu C, Baker PJ, Smith JB, et al. An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals. Blood. 2007;109(9):3794–802.PubMedPubMedCentralCrossRef

63.

Bermejo DA, Jackson SW, Gorosito-Serran M, Acosta-Rodriguez EV, Amezcua-Vesely MC, Sather BD, et al. Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and Ahr that leads to IL-17 production by activated B cells. Nat Immunol. 2013;14(5):514–22.PubMedPubMedCentralCrossRef

64.

Yang R, Liu Y, Kelk P, Qu C, Akiyama K, Chen C, et al. A subset of IL-17(+) mesenchymal stem cells possesses anti-Candida albicans effect. Cell Res. 2013;23(1):107–21.PubMedCrossRef

65.

Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.PubMedPubMedCentralCrossRef

66.

Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133–41.PubMedPubMedCentralCrossRef

67.

Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med. 2016;22(3):230–41.PubMedCrossRef

68.

Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103(9):1345–52.PubMedPubMedCentralCrossRef

69.

Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–82.PubMedPubMedCentralCrossRef

70.

Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8.PubMedCrossRef

71.

Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9906):1705–13.PubMedCrossRef

72.

McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386(9999):1137–46.PubMedCrossRef

73.

Al-Sebaei MO, Daukss DM, Belkina AC, Kakar S, Wigner NA, Cusher D, et al. Role of Fas and Treg cells in fracture healing as characterized in the fas-deficient (lpr) mouse model of lupus. J Bone Miner Res. 2014;29(6):1478–91.PubMedCrossRef

74.

Croes M, Oner FC, van Neerven D, Sabir E, Kruyt MC, Blokhuis TJ, et al. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone. 2016;84:262–70.PubMedCrossRef

75.

Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, Kim HM, et al. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 2009;16(10):1332–43.PubMedCrossRef

76.

Kocic J, Santibanez JF, Krstic A, Mojsilovic S, Dordevic IO, Trivanovic D, et al. Interleukin 17 inhibits myogenic and promotes osteogenic differentiation of C2C12 myoblasts by activating ERK1,2. Biochim Biophys Acta. 2012;1823(4):838–49.PubMedCrossRef

77.

Kim YG, Park JW, Lee JM, Suh JY, Lee JK, Chang BS, et al. IL-17 inhibits osteoblast differentiation and bone regeneration in rat. Arch Oral Biol. 2014;59(9):897–905.PubMedCrossRef

78.

Osta B, Lavocat F, Eljaafari A, Miossec P. Effects of interleukin-17A on osteogenic differentiation of isolated human mesenchymal stem cells. Front Immunol. 2014;5:425.PubMedPubMedCentral

79.

Shaw AT, Maeda Y, Gravallese EM. IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis. Arthritis Res Ther. 2016;18(1):104.PubMedPubMedCentralCrossRef

80.

Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014;32:659–702.PubMedCrossRef

81.

Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17(7):765–74.PubMedCrossRef

82.

Denitsa D, Florian H, Matthias S. Mesenchymal stem cells and their cell surface receptors. Curr Rheumatol Rev. 2008;4(3):155–60.CrossRef

83.

Xu C, Hasan SS, Schmidt I, Rocha SF, Pitulescu ME, Bussmann J, et al. Arteries are formed by vein-derived endothelial tip cells. Nat Commun. 2014;5:5758.PubMedCrossRef

84.

Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–88.PubMedCrossRef

85.

Kohara H, Omatsu Y, Sugiyama T, Noda M, Fujii N, Nagasawa T. Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling. Blood. 2007;110(13):4153–60.PubMedCrossRef

86.

Molyneaux KA, Zinszner H, Kunwar PS, Schaible K, Stebler J, Sunshine MJ, et al. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development. 2003;130(18):4279–86.PubMedCrossRef

87.

Li Q, Zhang A, Tao C, Li X, Jin P. The role of SDF-1-CXCR4/CXCR7 axis in biological behaviors of adipose tissue-derived mesenchymal stem cells in vitro. Biochem Biophys Res Commun. 2013;441(3):675–80.PubMedCrossRef

88.

• Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813–23. This study demonstrated that CXCL12 expression in the injured bone recruits circulating mesenchymal cells to promote bone fracture healing.PubMedCrossRef

89.

Granero-Molto F, Weis JA, Miga MI, Landis B, Myers TJ, O'Rear L, et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells. 2009;27(8):1887–98.PubMedPubMedCentralCrossRef

90.

Kawakami Y, Ii M, Matsumoto T, Kuroda R, Kuroda T, Kwon SM, et al. SDF-1/CXCR4 axis in Tie2-lineage cells including endothelial progenitor cells contributes to bone fracture healing. J Bone Miner Res. 2015;30(1):95–105.PubMedCrossRef

91.

Toupadakis CA, Wong A, Genetos DC, Chung DJ, Murugesh D, Anderson MJ, et al. Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair. J Orthop Res. 2012;30(11):1853–9.PubMedPubMedCentralCrossRef

92.

Ho CY, Sanghani A, Hua J, Coathup M, Kalia P, Blunn G. Mesenchymal stem cells with increased stromal cell-derived factor 1 expression enhanced fracture healing. Tissue Eng Part A. 2015;21(3-4):594–602.PubMedCrossRef

93.

Dennis EA, Norris PC. Eicosanoid storm in infection and inflammation. Nat Rev Immunol. 2015;15(8):511–23.PubMedPubMedCentralCrossRef

94.

Simon AM, Manigrasso MB, O'Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002;17(6):963–76.PubMedCrossRef

95.

Naik AA, Xie C, Zuscik MJ, Kingsley P, Schwarz EM, Awad H, et al. Reduced COX-2 expression in aged mice is associated with impaired fracture healing. J Bone Miner Res. 2009;24(2):251–64.PubMedCrossRef

96.

Xie C, Liang B, Xue M, Lin AS, Loiselle A, Schwarz EM, et al. Rescue of impaired fracture healing in COX-2-/- mice via activation of prostaglandin E2 receptor subtype 4. Am J Pathol. 2009;175(2):772–85.PubMedPubMedCentralCrossRef

97.

Tanaka M, Sakai A, Uchida S, Tanaka S, Nagashima M, Katayama T, et al. Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Bone. 2004;34(6):940–8.PubMedCrossRef

98.

Zhang M, Ho HC, Sheu TJ, Breyer MD, Flick LM, Jonason JH, et al. EP1(-/-) mice have enhanced osteoblast differentiation and accelerated fracture repair. J Bone Miner Res. 2011;26(4):792–802.PubMedCrossRef

99.

Kolev M, Le Friec G, Kemper C. Complement--tapping into new sites and effector systems. Nat Rev Immunol. 2014;14(12):811–20.PubMedCrossRef

100.

Rutkowski MJ, Sughrue ME, Kane AJ, Ahn BJ, Fang S, Parsa AT. The complement cascade as a mediator of tissue growth and regeneration. Inflamm Res. 2010;59(11):897–905.PubMedPubMedCentralCrossRef

101.

Ignatius A, Schoengraf P, Kreja L, Liedert A, Recknagel S, Kandert S, et al. Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1beta. J Cell Biochem. 2011;112(9):2594–605.PubMedPubMedCentralCrossRef

102.

Ehrnthaller C, Huber-Lang M, Nilsson P, Bindl R, Redeker S, Recknagel S, et al. Complement C3 and C5 deficiency affects fracture healing. PLoS One. 2013;8(11), e81341.PubMedPubMedCentralCrossRef

103.

Hernigou P, Pariat J. History of internal fixation with plates (part 2): new developments after World War II; compressing plates and locked plates. Int Orthop. 2016.

Title: Osteoimmunology in Bone Fracture Healing
Authors: Takehito Ono
Hiroshi Takayanagi
Publication date: 01-08-2017
Publisher: Springer US
Published in: Current Osteoporosis Reports / Issue 4/2017
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI: https://doi.org/10.1007/s11914-017-0381-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Osteoimmunology in Bone Fracture Healing

Abstract

Purpose of Review

Recent Findings

Summary

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

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