Abstract
For patients who are known to have an impaired immune system, bone healing is often impaired. Therefore, it has been suggested that an effectively functioning immune system will have an influence on the quality of bone healing. Here, we demonstrate that cells within the fracture hematoma of immunologically restricted patients (1) exhibit a disturbed osteogenic differentiation (normal SPP1 but diminished RUNX2 expression), (2) show a strong inflammatory reaction (high IL8 and CXCR4), and (3) react on local hypoxia (high expression of HIF1A) but with inadequate target gene responses (diminished LDHA and PGK1 expression). Thus, it is already within the early inflammatory phase of fracture healing that the local gene expression in fracture hematomas of immunologically restricted patients points toward a critical regeneration.
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Schmidmaier G, Schwabe P, Wildemann B, Haas NP. Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury. 2007;38(Suppl 4):S35–41.
Taguchi K, Ogawa R, Migita M, Hanawa H, Ito H, Orimo H. The role of bone marrow-derived cells in bone fracture repair in a green fluorescent protein chimeric mouse model. Biochem Biophys Res Commun. 2005;331:31–6.
Phillips AM. Overview of the fracture healing cascade. Injury. 2005;36(Suppl 3):S5–7.
Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol. 2008;19:459–66.
Kolar P, Schmidt-Bleek K, Schell H, Gaber T, Toben D, Schmidmaier G, Perka C, Buttgereit F, Duda GN. The early fracture hematoma and its potential role in fracture healing. Tissue Eng Part B Rev. 2010;16:427–34.
Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F. Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do!. Ann Rheum Dis. 2005;64:971–80.
Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645–57.
Gaber T, Haupl T, Sandig G, Tykwinska K, Fangradt M, Tschirschmann M, Hahne M, Dziurla R, Erekul K, Lautenbach M, Kolar P, Burmester GR, Buttgereit F. Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis. J Rheumatol. 2009;36:2655–69.
Epari DR, Kassi JP, Schell H, Duda GN. Timely fracture-healing requires optimization of axial fixation stability. J Bone Joint Surg Am. 2007;89:1575–85.
Lienau J, Schell H, Epari DR, Schutze N, Jakob F, Duda GN, Bail HJ. CYR61 (CCN1) protein expression during fracture healing in an ovine tibial model and its relation to the mechanical fixation stability. J Orthop Res. 2006;24:254–62.
Bogoch ER, Moran EL. Bone abnormalities in the surgical treatment of patients with rheumatoid arthritis. Clin Orthop Relat Res. 1999;366:8–21.
Dominiak B, Oxberry W, Chen P. Study on a nonhealing fracture from a patient with systemic lupus erythematosus and its pathogenetic mechanisms. Ultrastruct Pathol. 2005;29:107–20.
Follak N, Kloting I, Merk H. Influence of diabetic metabolic state on fracture healing in spontaneously diabetic rats. Diabetes Metab Res Rev. 2005;21:288–96.
Kidder LS, Chen X, Schmidt AH, Lew WD. Osteogenic protein-1 overcomes inhibition of fracture healing in the diabetic rat: a pilot study. Clin Orthop Relat Res. 2009;467:3249–56.
Stromqvist B. Hip fracture in rheumatoid arthritis. Acta Orthop Scand. 1984;55:624–8.
Tyndall WA, Beam HA, Zarro C, O’Connor JP, Lin SS. Decreased platelet derived growth factor expression during fracture healing in diabetic animals. Clin Orthop Relat Res 2003;408:319–30.
Kolar P, Gaber T, Perka C, Duda GN, Buttgereit F. Human early fracture hematoma is characterized by inflammation and hypoxia. Clin Orthop Relat Res. 2011. Epub ahead of print.
Busti AJ, Hooper JS, Amaya CJ, Kazi S. Effects of perioperative antiinflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy. 2005;25:1566–91.
Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA. Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing. 2006;3:10.
Ishikawa M, Nishioka M, Hanaki N, Miyauchi T, Kashiwagi Y, Kawasaki Y, Miki H, Kagawa H, Ioki H, Nakamura Y. Postoperative host responses in elderly patients after gastrointestinal surgery. Hepatogastroenterology. 2006;53:730–5.
Smith RM. Immunity, trauma and the elderly. Injury. 2007;38:1401–4.
Woodland DL, Blackman MA. Immunity and age: living in the past? Trends Immunol. 2006;27:303–7.
Kang SC, Matsutani T, Choudhry MA, Schwacha MG, Rue LW, Bland KI, Chaudry IH. Are the immune responses different in middle-aged and young mice following bone fracture, tissue trauma and hemorrhage? Cytokine. 2004;26:223–30.
Arason GJ, Jorgensen GH, Ludviksson BR. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010;71:317–28.
Yu D, Vinuesa CG. Multiple checkpoints keep follicular helper T cells under control to prevent autoimmunity. Cell Mol Immunol. 2010;7:198–203.
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The authors thank Manuela Jakstadt for her excellent technical assistance.
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Hoff, P., Gaber, T., Schmidt-Bleek, K. et al. Immunologically restricted patients exhibit a pronounced inflammation and inadequate response to hypoxia in fracture hematomas. Immunol Res 51, 116–122 (2011). https://doi.org/10.1007/s12026-011-8235-9
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DOI: https://doi.org/10.1007/s12026-011-8235-9