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Interleukin-6 as possible early marker of stress response after femoral fracture

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Abstract

Bone fracture healing is a complex process which at best results in full recovery of function and structure of injured bone tissue, but all the mechanisms involved in this process, and their mutual interaction, are not fully understood. Despite advancement of surgical procedures, this type of fractures is still a major public health concern. In the last few decades, a lot of attention is focused on the oxygen-free radicals and inflammatory response markers as important factors of skeletal injury. Thus, the aim of the present study was to follow the changes in redox balance and inflammatory response in elderly patients with femoral fractures during the earliest stages of fracture healing, by measuring the values of the observed markers immediately after fracture, as well as the first, third, and seventh postoperative day. Present study was performed on a group of 65 elderly patients with femoral neck fractures, recruited from the Orthopedic Clinic, Clinical Centre Kragujevac in the period from February to May 2015. Redox status was measured spectrophotometrically and evaluated by measuring the levels of index of lipid peroxidation (measured as TBARS), nitrite (NO2 −), superoxide anion radical (O2 −), and hydrogen peroxide (H2O2) in plasma, while activities of corresponding antioxidative enzymes, catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) were measured in erythrocytes. The cytokine concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were determined in plasma, using ELISA assays specific for human cytokines. Our study showed that redox status and TNF-α in elderly patients with femoral fractures did not show statistically significant changes during the early phase of fracture healing. On the other hand, IL-6 increased statistically in first day after intervention. This preliminary study has shown our observations, and we hope that these results may help in better understanding mechanisms which are included at fracture healing. More importantly, this study attempted to create a platform for further research.

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References

  1. Diamantopoulos AP, Rohde G, Johnsrud I, Skoie IM, Johnsen V, Hochberg M, Haugeberg G (2012) Incidence rates of fragility hip fracture in middle-aged and elderly men and women in southern Norway. Age Ageing 41:86–92

    Article  PubMed  Google Scholar 

  2. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB (2009) Incidence and mortality of hip fractures in the United States. JAMA 302:1573–1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Icks A, Haastert B, Glaeske G, Stumpf U, Windolf J, Hoffmann F (2012) Correction factor for the analysis of the hip fracture incidence-differences between age, sex, region, and calendar year. Wien Klin Wochenschr 124:391–394

    Article  PubMed  Google Scholar 

  4. Gullberg B, Johnell O, Kanis JA (1997) Worldwide projections for hip fracture. Osteoporos Int 7:407–413

    Article  CAS  PubMed  Google Scholar 

  5. Kannus P, Parkkari J, Sievanen H, Heinonen A, Vuori I, Jarvinen M (1996) Epidemiology of hip fractures. Bone 18:57–63

    Article  Google Scholar 

  6. Fernández-Ruiz M, Guerra-Vales JM, Trincado R, Medrano MJ, Benito-León J, Bermejo-Pareja F (2014) Hip fracture in three elderly populations of central Spain: data from the NEDICES study. Intern Emerg Med 9:33–41

    Article  PubMed  Google Scholar 

  7. Papakostidis C, Bhandari M, Giannoudis PV (2013) Distraction osteogenesis in the treatment of long bone defects of the lower limbs: effectiveness, complications and clinical results; a systematic review and meta-analysis. Bone Joint J 95-B:1673–1680

    Article  CAS  PubMed  Google Scholar 

  8. Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F (2010) The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J Endocrinol 205:201–210

    Article  CAS  PubMed  Google Scholar 

  9. Rubin CD (2012) Evaluation and management of hip fracture risk in the aged. Am J Med Sci 343:233–242

    Article  PubMed  Google Scholar 

  10. Gajdobranski D, Zivković D (2003) Disorders in fracture healing. Med Pregl 56:146–151

    Article  PubMed  Google Scholar 

  11. Shuid AN, Mohamad S, Muhammad N et al (2011) Effects of α-tocopherol on the early phase of osteoporotic fracture healing. J Orthop Res 29:1732–1738

    Article  CAS  PubMed  Google Scholar 

  12. Wehner T, Gruchenberg K, Bindl R, Recknagel S, Steiner M, Ignatius A, Claes L (2014) Temporal delimitation of the healing phases via monitoring of fracture callus stiffness in rats. J Orthop Res 32:1589–1595

    Article  PubMed  Google Scholar 

  13. Ketenjian AY, Jafri AM, Arsenis C (1978) Studies on the mechanism of callus cartilage differentiation and calcification during fracture healing. Orthop Clin N Am 9:43–65

    CAS  Google Scholar 

  14. Hapuarachchi KS, Ahluwalia RS, Bowditch MG (2014) Neck of femur fractures in the over 90s: a select group of patients who require prompt surgical intervention for optimal results. J Orthop Traumatol 15:13–19

    Article  CAS  PubMed  Google Scholar 

  15. Zhang YB, Zhong ZM, Hou G, Jiang H, Chen JT (2011) Involvement of oxidative stress in age-related bone loss. J Surg Res 169:e37–e42

    Article  CAS  PubMed  Google Scholar 

  16. Sheweita SA, Khoshhal KI (2007) Calcium metabolism and oxidative stress in bonebfractures: role of antioxidants. Curr Drug Metab 8:519–525

    Article  CAS  PubMed  Google Scholar 

  17. Rangan U, Bulkley GB (1993) Prospects for treatment of free radical-mediated tissue injury. Br Med Bull 49:700–718

    Article  CAS  PubMed  Google Scholar 

  18. Banfi G, Iorio EL, Corsi MM (2008) Oxidative stress, free radicals and bone remodeling. Clin Chem Lab Med 46:1550–1555

    CAS  PubMed  Google Scholar 

  19. Keskin D, Kiziltunc A (2015) Reduction of total antioxidant capacity after femoral fracture. Acta Chir Orthop Traumatol Cechoslov 82:293–295

    CAS  Google Scholar 

  20. Maggio D, Barabani M, Pierandrei M, Polidori MC, Catani M, Mecocci P, Senin U, Pacifici R, Cherubini A (2003) Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab 88:1523–1527

    Article  CAS  PubMed  Google Scholar 

  21. Wang Z, Ehnert S, Ihle C, Schyschka L, Pscherer S, Nussler NC, Braun KF, Van Griensven M, Wang G, Burgkart R, Stöckle U, Gebhard F, Vester H, Nussler AK (2014) Increased oxidative stress response in granulocytes from older patients with a hip fracture may account for slow regeneration. Oxid Med Cell Longev 2014:819847

    PubMed  PubMed Central  Google Scholar 

  22. Reilly PM, Schiller HJ, Bulkley GB (1991) Pharmacologic approach to tissue injury mediated by free radicals and other reactive oxygen metabolites. Am J Surg 161:488–503

    Article  CAS  PubMed  Google Scholar 

  23. Basu S, Michaëlsson K, Olofsson H, Johansson S, Melhus H (2001) Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun 288:275–279

    Article  CAS  PubMed  Google Scholar 

  24. Jyoti A, Singh S, Mukhopadhyay B, Gavel R, Mishra SP (2015) Free radicals and antioxidant status in chronic osteomyelitis patients: a case control study. J Clin Diagn Res 4:8–10

    Google Scholar 

  25. Nakase T, Takaoka K, Masuhara K, Shimizu K, Yoshikawa H, Ochi T (1997) Interleukin-1β enhance and tumor necrosis factor-α inhibits bone morphogenetic protein-2-induced alkaline phosphatase activity in MC3T3-E1 osteoblastic cells. Bone 21:17–21

    Article  CAS  PubMed  Google Scholar 

  26. Nanes MS (2003) Tumor necrosis factor-α: molecular and cellular mechanisms in skeletal pathology. Gene 321:1–15

    Article  CAS  PubMed  Google Scholar 

  27. Craig S, Roberts CS, Pape HC, Jones AL, Malkani AL, Rodriguez JL, Giannoudis PV (2005) Damage control orthopaedics. Evolving concepts in the treatment of patients who have sustained orthopaedic trauma. J Bone Joint Surg Am 87:434–449

    Article  Google Scholar 

  28. Sears BW, Strover MD, Callaci J (2009) Pathoanatomy and clinical correlation of the immunoinflamatory response following orthopaedic trauma. J AAOS 17:255–265

    Google Scholar 

  29. Reikeras O (2010) Immune depression in musculoskeletal trauma. Inflamm Res 59:409–414

    Article  CAS  PubMed  Google Scholar 

  30. Biffl W, Moore EE, Moore FA, Peterson VM (1996) Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation? Ann Surg 224:647–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Marcucci G, Brandi ML. Rare causes of osteoporosis. Clin Cases Miner Bone Metab. 2015 May-Aug;12(2):151–156

    PubMed  PubMed Central  Google Scholar 

  32. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  33. Green LC, Wagner DA, Glogowski J, Skipper PI, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal Biochem 126:131–138

    Article  CAS  PubMed  Google Scholar 

  34. Auclair C, Voisin E (1985) Nitrobluetetrazolium reduction. In: Greenwald RA (ed) Handbook of methods for oxygen radical research. CRP Press, Boca Raton, pp 123–132

    Google Scholar 

  35. Pick E, Keisari Y (1980) A simple colometric method for the measurement of hydrogen peroxide by cells in culture. J Immunol Methods 38:161–170

    Article  CAS  PubMed  Google Scholar 

  36. McCord JM, Fridovich I (1969) The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and oxygen. J Biol Chem 244:6056–6063

    CAS  PubMed  Google Scholar 

  37. Beutler E (1982) Catalase. In: Beutler E (ed) Red cell metabolism, a manual of biochemical methods. Grune and Stratton, New York, pp 105–106

    Google Scholar 

  38. Misra HP, Fridovich I (1972) The role of superoxide anion in theautoxidation of epinephrine and a simple assay for superoxidedismutase. J BiolChem 247:3170–3175

    CAS  Google Scholar 

  39. Beutler E (1975) Reduced glutathione (GSH). In: Beutler E (ed) Red cell metabolism, a manual of biochemical methods. Grune and Stratton, New York, pp 112–114

    Google Scholar 

  40. Radosavljevic G, Jovanovic I, Majstorovic I, Mitrovic M, Lisnic VJ, Arsenijevic N, Jonjic S, Lukic ML (2011) Deletion of galectin-3 in the host attenuates metastasis of murine melanoma by modulating tumor adhesion and NK cell activity. Clin Exp Metastasis 28:451–462

    Article  CAS  PubMed  Google Scholar 

  41. Crowther JR (1995) ELISA. Theory and practice. Methods Mol Biol 42:1–218

    CAS  PubMed  Google Scholar 

  42. Halliwell B, Cross CE (1994) Oxygen-derived species: their relation to human disease and environmental stress. Environ Health Perspect 102(Suppl 10):5–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ilyas A, Odatsu T, Shah A, Monte F, Kim HK, Kramer P, Aswath PB, Varanasi VG (2016) Amorphous silica: a new antioxidant role for rapid critical-sized bone defect healing. Adv Healthc Mater 5:2199–2213

  44. Ardura JA, Portal-Núñez S, Castelbón-Calvo I, Martínez de Toda I, De la Fuente M, Esbrit P (2016) Parathyroid hormone-related protein protects osteoblastic cells from oxidative stress by activation of MKP1 phosphatase. J Cell Physiol 9999:1–12

    Google Scholar 

  45. Ono K, Han J (2000) The p38 signal transduction pathway: activation and function. Cell Signal 12:1–13

    Article  CAS  PubMed  Google Scholar 

  46. Gokturk E, Turgut A, Baycu C, Gunal J, Seber S, Gulbas Z (1995) Oxygen free radicals impair fracture healing in rats. Acta Orthop Scand 66:473–475

    Article  CAS  PubMed  Google Scholar 

  47. Prasad G, Dhillon MS, Khullar M, Nagi ON (2003) Evaluation of oxidative stress after fractures. A preliminary study. Acta Orthop Belg 69:546–551

    PubMed  Google Scholar 

  48. Lafforgue P (2006) Pathophysiology and natural history of avascular necrosis of bone. Joint Bone Spine 73:500–507

    Article  CAS  PubMed  Google Scholar 

  49. Rangan U, Bulkley GB (1993) Prospects for treatment of free radical mediated tissue injury. Br Med Bull 49:700–718

    Article  CAS  PubMed  Google Scholar 

  50. Guemouri L, Artur Y, Herbeth B, Jeandel C, Cuny G, Siest G (1991) Biological variability of superoxide dismutase, glutathione peroxidase, and catalase in blood. Clin Chem 37:1932–1937

    CAS  PubMed  Google Scholar 

  51. Pesic G, Jeremic J, Stojic I, Vranić A, Cankovic M, Nikolic T, Jeremic N, Matic A, Srejovic I, Zivkovic V, Jakovljevic V (2016) Redox status in patients with femoral neck fractures. Ser J Exp Clin Res 17:1–1

    Article  Google Scholar 

  52. Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I (2016) Immunology of osteoporosis: a mini-review. Gerontology 62:128–137

    Article  CAS  PubMed  Google Scholar 

  53. Ishimi Y, Miyuara C, Jin CH et al (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303

    CAS  PubMed  Google Scholar 

  54. Beeton CA, Chatfield D, Brooks RA, Rushton N (2004) Circulating levels of interleukin-6 and its soluble receptor in patients with head injury and fracture. Bone Joint J 86:912–917

    Article  CAS  Google Scholar 

  55. Volpin G, Cohen M, Assaf M, Meir T, Katz R, Pollack S (2014) Cytokine levels (IL-4, IL-6, IL-8 and TGFβ) as potential biomarkers of systemic inflammatory response in trauma patients. Int Orthop 38:1303–1309

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Camacho NP, Bostrom MP (2007) Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone 41:928–936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Roy B, Curtis ME, Fears LS, Nahashon SN, Fentress HM. Molecular mechanisms of obesity-induced osteoporosis and muscle atrophy. Front Physiol 2016 Sep 29;7:439.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Wang TT, He CQ, Yu XJ. Pro-Inflammation Cytokines: New Potential Therapeutic Targets for Obesity-Related Bone Disorders. Curr Drug Targets 2017 Jan 4.

  59. Yamasaki M, Hasegawa S, Imai M, Takahashi N, Fukui T. High-fat diet-induced obesity stimulates ketone body utilization in osteoclasts of the mouse bone. Biochem Biophys Res Commun. 2016 Apr 29;473(2):654–661.

    Article  CAS  PubMed  Google Scholar 

  60. Lange J, Sapozhnikova A, Lu C et al (2010) Action of IL-1β during fracture healing. J Orthop Res 28:778–784

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Marino M, Palmieri G, Peruzzi M, Scuderi F, Bartoccioni E (2015) A study of inflammatory/necrosis biomarkers in the fracture of the femur treated with proximal femoral nail antirotation. Mediators Inflamm. doi:10.1155/2015/189864.

    Google Scholar 

  62. Turk CY, Halici M, Guney A, Akgun H, Sahin V, Muhtaroglu S (2004) Promotion of fracture healing by vitamin E in rats. J Int Med Res 32:507–512

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Orthopedic and Traumatology Clinic, Podgorica, Montenegro

    Goran Pesic

  2. Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Jovana Jeremic, Tamara Nikolic, Aleksandra Vranic & Jovana Bradic

  3. Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Vladimir Zivkovic, Ivan Srejovic & Vladimir Jakovljevic

  4. Clinic of Orthopedic Surgery, Clinical Center of Kragujevac, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Branko Ristic, Aleksandar Matic & Nikola Prodanovic

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  1. Goran Pesic
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Correspondence to Vladimir Jakovljevic.

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Pesic, G., Jeremic, J., Nikolic, T. et al. Interleukin-6 as possible early marker of stress response after femoral fracture. Mol Cell Biochem 430, 191–199 (2017). https://doi.org/10.1007/s11010-017-2967-3

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