Osteoimmunology of Fracture Healing: A Brief Review on the Immune Systems’ Cellular Milieu Role in Bone Injury

  • Dimitrios A. Flevas
  • Maria G. Papageorgiou
  • Panagiotis Drakopoulos
  • Ioannis K. Triantafyllopoulos
  • George I. Lambrou
Keywords: Fracture Healing, Immune System, Bone Fracture, Bone Healing, Immune Cells

Abstract

Bone fracture healing is the most common medical treatment in the usual clinical practice. Bone has the unique property for self-healing, which is in addition to the ability of not forming a scar. Following fracture, a chain of events takes place, which include the activation of healing processes in both the cellular and tissue level. These events, lead to a full bridging of the gap between the two bone-ends of the fracture. In that process the immune system is active and the immune cells are known to play a significant role. The process of fracture healing can be divided in three main steps; these are sequential in nature and independent. The first phase includes the inflammation phase, which involves the acute activation of the immune system, the second phase includes the repair phase, which involves the recruitment of mesenchymal progenitor cells differentiating to chondrocytes and the final phase involves remodeling, where osteocytes are recruited in order to form the new bone. In conclusion, immunity serves as the initial responder at the skeletal damaged site, restores the vasculature, and initiates cascades of signals to recruit cells to carry out the repair processes. Therefore, it is believed that the immune system can be considered as a promising therapeutic target for bone fracture healing.

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Author Biographies

Dimitrios A. Flevas

Postgraduate Program “Metabolic Bones Diseases”, National and Kapodistrian University of Athens, Medical School, Mikras Asias 75, 11527, Goudi, Athens, Greece

Laboratory for the Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Medical School, Nikis 2, 14561, Kifissia, Athens, Greece

Maria G. Papageorgiou

2nd Department of Internal Medicine, Section of Medical Oncology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece

Panagiotis Drakopoulos

Postgraduate Program “Metabolic Bones Diseases”, National and Kapodistrian University of Athens, Medical School, Mikras Asias 75, 11527, Goudi, Athens, Greece

Ioannis K. Triantafyllopoulos

Postgraduate Program “Metabolic Bones Diseases”, National and Kapodistrian University of Athens, Medical School, Mikras Asias 75, 11527, Goudi, Athens, Greece

Laboratory for the Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Medical School, Nikis 2, 14561, Kifissia, Athens, Greece

Head of the 5th Orthopaedic Department, HYGEIA Private Hospital, Athens, Greece

George I. Lambrou

Postgraduate Program “Metabolic Bones Diseases”, National and Kapodistrian University of Athens, Medical School, Mikras Asias 75, 11527, Goudi, Athens, Greece

Laboratory for the Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Medical School, Nikis 2, 14561, Kifissia, Athens, Greece

Choremeio Research Laboratory, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, Thivon & Levadeias 8, 11527, Goudi, Athens, Greece

References

1. Baht GS, Vi L, Alman BA. The Role of the Immune Cells in Fracture Healing. Current osteoporosis reports. 2018;16(2):138-45. doi.10.1007/s11914-018-0423-2.
2. Tzioupis C, Giannoudis PV. Prevalence of long-bone non-unions. Injury. 2007;38 Suppl 2:S3-9. doi.10.1016/s0020-1383(07)80003-9.
3. Ono T, Takayanagi H. Osteoimmunology in Bone Fracture Healing. Current osteoporosis reports. 2017;15(4):367-75. doi.10.1007/s11914-017-0381-0.
4. Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nature reviews Rheumatology. 2009;5(12):667-76. doi.10.1038/nrrheum.2009.217.
5. El-Jawhari JJ, Jones E, Giannoudis PV. The roles of immune cells in bone healing; what we know, do not know and future perspectives. Injury. 2016;47(11):2399-406. doi.10.1016/j.injury.2016.10.008.
6. Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, et al. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiological reviews. 2017;97(4):1295-349. doi.10.1152/physrev.00036.2016.
7. Horton JE, Raisz LG, Simmons HA, Oppenheim JJ, Mergenhagen SE. Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science. 1972;177(4051):793-5. doi.10.1126/science.177.4051.793.
8. Arron JR, Choi Y. Bone versus immune system. Nature. 2000;408(6812):535-6. doi.10.1038/35046196.
9. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408(6812):600-5. doi.10.1038/35046102.
10. Lorenzo J, Horowitz M, Choi Y. Osteoimmunology: interactions of the bone and immune system. Endocrine reviews. 2008;29(4):403-40. doi.10.1210/er.2007-0038.
11. Giannopoulou C, Martinelli-Klay CP, Lombardi T. Immunohistochemical expression of RANKL, RANK and OPG in gingival tissue of patients with periodontitis. Acta odontologica Scandinavica. 2012;70(6):629-34. doi.10.3109/00016357.2011.645064.
12. Thiele S, Rauner M, Goes P. Recent advances in periodontitis, a prototypic osteo-immunological.
13. Schneider PS, Sandman E, Martineau PA. Osteoimmunology: Effects of Standard Orthopaedic Interventions on Inflammatory Response and Early Fracture Healing. The Journal of the American Academy of Orthopaedic Surgeons. 2018;26(10):343-52. doi.10.5435/jaaos-d-16-00646.
14. Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nature reviews Rheumatology. 2015;11(1):45-54. doi.10.1038/nrrheum.2014.164.
15. 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. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2010;28(3):397-402. doi.10.1002/jor.21008.
16. Monfoulet L, Rabier B, Chassande O, Fricain JC. Drilled hole defects in mouse femur as models of intramembranous cortical and cancellous bone regeneration. Calcified tissue international. 2010;86(1):72-81. doi.10.1007/s00223-009-9314-y.
17. Bissinger O, Kreutzer K, Götz 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 musculoskeletal disorders. 2016;17(1):383. doi.10.1186/s12891-016-1241-2.
18. Holstein JH, Klein M, Garcia P, Histing T, Culemann U, Pizanis A, et al. Rapamycin affects early fracture healing in mice. British journal of pharmacology. 2008;154(5):1055-62. doi.10.1038/bjp.2008.167.
19. Satoh K, Mark H, Zachrisson P, Rydevik B, Byröd G, Kikuchi S, et al. Effect of methotrexate on fracture healing. Fukushima journal of medical science. 2011;57(1):11-8. doi.10.5387/fms.57.11.
20. Richardson J, Hill AM, Johnston CJ, McGregor A, Norrish AR, Eastwood D, et al. Fracture healing in HIV-positive populations. The Journal of bone and joint surgery British volume. 2008;90(8):988-94. doi.10.1302/0301-620x.90b8.20861.
21. Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2001;16(6):1004-14. doi.10.1359/jbmr.2001.16.6.1004.
22. Ozaki A, Tsunoda M, Kinoshita S, Saura R. Role of fracture hematoma and periosteum during fracture healing in rats: interaction of fracture hematoma and the periosteum in the initial step of the healing process. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2000;5(1):64-70. doi.10.1007/s007760050010.
23. Timlin M, Toomey D, Condron C, Power C, Street J, Murray P, et al. Fracture hematoma is a potent proinflammatory mediator of neutrophil function. The Journal of trauma. 2005;58(6):1223-9. doi.10.1097/01.ta.0000169866.88781.f1.
24. Meert KL, Ofenstein JP, Sarnaik AP. Altered T cell cytokine production following mechanical trauma. Annals of clinical and laboratory science. 1998;28(5):283-8.
25. 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. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(6):1478-91. doi.10.1002/jbmr.2169.
26. Motsitsi NS. Management of infected nonunion of long bones: the last decade (1996-2006). Injury. 2008;39(2):155-60. doi.10.1016/j.injury.2007.08.032.
27. Roldán JC, Jepsen S, Miller J, Freitag S, Rueger DC, Açil Y, et al. Bone formation in the presence of platelet-rich plasma vs. bone morphogenetic protein-7. Bone. 2004;34(1):80-90. doi.10.1016/j.bone.2003.09.011.
28. Jingushi S, Scully SP, Joyce ME, Sugioka Y, Bolander ME. Transforming growth factor-beta 1 and fibroblast growth factors in rat growth plate. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 1995;13(5):761-8. doi.10.1002/jor.1100130516.
29. Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury. 2005;36(12):1392-404. doi.10.1016/j.injury.2005.07.019.
30. Dülgeroglu TC, Metineren H. Evaluation of the Effect of Platelet-Rich Fibrin on Long Bone Healing: An Experimental Rat Model. Orthopedics. 2017;40(3):e479-e84. doi.10.3928/01477447-20170308-02.
31. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. The American journal of pathology. 1975;78(1):71-100.
32. Vannella KM, Wynn TA. Mechanisms of Organ Injury and Repair by Macrophages. Annual review of physiology. 2017;79:593-617. doi.10.1146/annurev-physiol-022516-034356.
33. Wu AC, Raggatt LJ, Alexander KA, Pettit AR. Unraveling macrophage contributions to bone repair. BoneKEy reports. 2013;2:373. doi.10.1038/bonekey.2013.107.
34. Alexander KA, Chang MK, Maylin ER, Kohler T, Müller R, Wu AC, et al. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;26(7):1517-32. doi.10.1002/jbmr.354.
35. Baht GS, Silkstone D, Vi L, Nadesan P, Amani Y, Whetstone H, et al. Exposure to a youthful circulaton rejuvenates bone repair through modulation of β-catenin. Nature communications. 2015;6:7131. doi.10.1038/ncomms8131.
36. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445-55. doi.10.1038/nature12034.
37. Mackaness GB. Cellular resistance to infection. The Journal of experimental medicine. 1962;116(3):381-406. doi.10.1084/jem.116.3.381.
38. Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases. International journal of biological sciences. 2014;10(5):520-9. doi.10.7150/ijbs.8879.
39. 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. 2018;106:78-89. doi.10.1016/j.bone.2015.10.019.
40. 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. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015;30(6):1090-102. doi.10.1002/jbmr.2422.
41. 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. Journal of immunology (Baltimore, Md : 1950). 2008;181(2):1232-44. doi.10.4049/jimmunol.181.2.1232.
42. Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L. Neutrophils: molecules, functions and pathophysiological aspects. Laboratory investigation; a journal of technical methods and pathology. 2000;80(5):617-53. doi.10.1038/labinvest.3780067.
43. Furze RC, Rankin SM. Neutrophil mobilization and clearance in the bone marrow. Immunology. 2008;125(3):281-8. doi.10.1111/j.1365-2567.2008.02950.x.
44. Bastian OW, Koenderman L, Alblas J, Leenen LP, Blokhuis TJ. Neutrophils contribute to fracture healing by synthesizing fibronectin+ extracellular matrix rapidly after injury. Clinical immunology (Orlando, Fla). 2016;164:78-84. doi.10.1016/j.clim.2016.02.001.
45. Segal AW. How neutrophils kill microbes. Annual review of immunology. 2005;23:197-223. doi.10.1146/annurev.immunol.23.021704.115653.
46. Xian CJ, Zhou FH, McCarty RC, Foster BK. Intramembranous ossification mechanism for bone bridge formation at the growth plate cartilage injury site. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2004;22(2):417-26. doi.10.1016/j.orthres.2003.08.003.
47. 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. doi.10.1371/journal.pone.0040044.
48. 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. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;26(1):113-24. doi.10.1002/jbmr.185.
49. El Khassawna T, Serra A, Bucher CH, Petersen A, Schlundt C, Könnecke I, et al. T Lymphocytes Influence the Mineralization Process of Bone. Frontiers in immunology. 2017;8:562. doi.10.3389/fimmu.2017.00562.
50. Könnecke 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. doi.10.1016/j.bone.2014.03.052.
51. Bosselut R. CD4/CD8-lineage differentiation in the thymus: from nuclear effectors to membrane signals. Nature reviews Immunology. 2004;4(7):529-40. doi.10.1038/nri1392.
52. Kitagawa Y, Ohkura N, Sakaguchi S. Molecular determinants of regulatory T cell development: the essential roles of epigenetic changes. Frontiers in immunology. 2013;4:106. doi.10.3389/fimmu.2013.00106.
53. Ciofani M, Zúñiga-Pflücker JC. Determining γδ versus αß T cell development. Nature reviews Immunology. 2010;10(9):657-63. doi.10.1038/nri2820.
54. Vantourout P, Hayday A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nature reviews Immunology. 2013;13(2):88-100. doi.10.1038/nri3384.
55. Bonneville M, O’Brien RL, Born WK. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nature reviews Immunology. 2010;10(7):467-78. doi.10.1038/nri2781.
56. Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, et al. IL-17-producing γδ T cells enhance bone regeneration. Nature communications. 2016;7:10928. doi.10.1038/ncomms10928.
57. 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. Science translational medicine. 2013;5(177):177ra36. doi.10.1126/scitranslmed.3004754.
58. Shen P, Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines. Nature reviews Immunology. 2015;15(7):441-51. doi.10.1038/nri3857.
59. 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. Clinical and experimental pharmacology & physiology. 2017;44(4):455-62. doi.10.1111/1440-1681.12719.
60. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402(6759):304-9. doi.10.1038/46303.
61. 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. The American journal of pathology. 2013;182(5):1501-8. doi.10.1016/j.ajpath.2013.01.046.
62. 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 : acta pathologica, microbiologica, et immunologica Scandinavica. 2015;123(11):975-85. doi.10.1111/apm.12439.
63. Chaplin DD. Overview of the immune response. The Journal of allergy and clinical immunology. 2010;125(2 Suppl 2):S3-23. doi.10.1016/j.jaci.2009.12.980.
64. Hauser CJ, Joshi P, Jones Q, Zhou X, Livingston DH, Lavery RF. Suppression of natural killer cell activity in patients with fracture/soft tissue injury. Archives of surgery (Chicago, Ill : 1960). 1997;132(12):1326-30. doi.10.1001/archsurg.1997.01430360072013.
65. Söderström K, Stein E, Colmenero P, Purath U, Müller-Ladner U, de Matos CT, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(29):13028-33. doi.10.1073/pnas.1000546107.
66. Almeida CR, Caires HR, Vasconcelos DP, Barbosa MA. NAP-2 Secreted by Human NK Cells Can Stimulate Mesenchymal Stem/Stromal Cell Recruitment. Stem cell reports. 2016;6(4):466-73. doi.10.1016/j.stemcr.2016.02.012.
67. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nature reviews Rheumatology. 2012;8(3):133-43. doi.10.1038/nrrheum.2012.1.
68. Mizuno K, Mineo K, Tachibana T, Sumi M, Matsubara T, Hirohata K. The osteogenetic potential of fracture haematoma. Subperiosteal and intramuscular transplantation of the haematoma. The Journal of bone and joint surgery British volume. 1990;72(5):822-9. doi.10.1302/0301-620x.72b5.2211764.
69. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nature reviews Immunology. 2015;15(1):30-44. doi.10.1038/nri3785.
70. Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(24):11924-8. doi.10.1073/pnas.90.24.11924.
71. 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 and rheumatism. 2006;54(1):158-68. doi.10.1002/art.21537.
72. 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. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2015;33(7):965-70. doi.10.1002/jor.22857.
73. Wallace A, Cooney TE, Englund R, Lubahn JD. Effects of interleukin-6 ablation on fracture healing in mice. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2011;29(9):1437-42. doi.10.1002/jor.21367.
74. 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. doi.10.1016/j.bone.2007.07.022.
75. Blüml S, Scheinecker C, Smolen JS, Redlich K. Targeting TNF receptors in rheumatoid arthritis. International immunology. 2012;24(5):275-81. doi.10.1093/intimm/dxs047.
76. 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. The Journal of clinical investigation. 2004;114(11):1603-11. doi.10.1172/jci20742.
77. 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. The EMBO journal. 1991;10(13):4025-31.
78. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nature medicine. 2007;13(2):156-63. doi.10.1038/nm1538.
79. 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. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2003;18(9):1584-92. doi.10.1359/jbmr.2003.18.9.1584.
80. Beringer A, Noack M, Miossec P. IL-17 in Chronic Inflammation: From Discovery to Targeting. Trends in molecular medicine. 2016;22(3):230-41. doi.10.1016/j.molmed.2016.01.001.
81. 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. Nature immunology. 2013;14(5):514-22. doi.10.1038/ni.2569.
82. 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. The Journal of experimental medicine. 2005;201(2):233-40. doi.10.1084/jem.20041257.
83. 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. Nature immunology. 2005;6(11):1133-41. doi.10.1038/ni1261.
84. 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 research. 2013;23(1):107-21. doi.10.1038/cr.2012.179.
85. 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 (London, England). 2013;382(9906):1705-13. doi.10.1016/s0140-6736(13)61134-4.
86. 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 (London, England). 2015;386(9999):1137-46. doi.10.1016/s0140-6736(15)61134-5.
87. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, et al. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(18):7260-4. doi.10.1073/pnas.87.18.7260.
88. Wu Y, Humphrey MB, Nakamura MC. Osteoclasts - the innate immune cells of the bone. Autoimmunity. 2008;41(3):183-94. doi.10.1080/08916930701693180.
89. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337-42. doi.10.1038/nature01658.
90. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. doi.10.1080/14653240600855905.
Published
2021-12-02