Abstract
Introduction
Several reports indicated that interleukin-6 (IL-6) and tumor necrosis factor α (TNF- α) play important regulatory roles in bone remodeling and homeostasis. In addition, receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) have been shown to be important regulators of osteoclastogenesis during bone remodeling, and their expressions were examined during fracture healing in a mouse model of tibial fracture. However, studies linking RANKL, OPG, IL-6 and TNF-α in patients with head injury and fracture are lacking.
Patients and methods
Within the first few hours of admission to hospital and at 4, 8, and 12 weeks after the injury, we evaluated changes in serum levels of RANKL, OPG, IL-6 and TNF-α in 24 male patients with a concomitant head injury and fracture and in 26 male patients with fracture only. These levels were compared with those found in 36 healthy controls.
Results
The RANKL/OPG ratios were found to significantly lower in patients with a concomitant head injury and fracture than in the controls immediately after admission and at 4, 8, and 12 weeks after the injury. In addition, RANKL/OPG ratios were significantly lower in patients with a concomitant head injury and fracture than in those with fracture at 8 and 12 weeks after the injury. The serum IL-6 levels were significantly higher in patients with a concomitant head injury and fracture than in the controls upon admission, and at 4, 8, and 12 weeks after the injury. Moreover, the serum IL-6 levels were significantly higher in patients with a head injury and fracture than in those with just a fracture at 4, 8, and 12 weeks after the injury.
Conclusions
Based on these changes in the profiles of RANKL, OPG, and IL-6 and the RANKL/OPG ratio, altered repair of a fracture can occur in patients with a concomitant head injury and fracture.
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References
Balto K, Sasaki H, Stashenko P (2001) Interleukin-6 deficiency increases inflammatory bone destruction. Infect Immun 69:744–750
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. J Bone Joint Surg Br 86:912–917
Black K, Garrett IR, Mundy GR (1991) Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology 128:2657–2659
Einhorn TA, Majeska RJ, Rush EB, Levine PM, Horowitz MC (1995) The expression of cytokine activity by fracture callus. J Bone Miner Res 10:1272–1281
Felver ME, Mezey E, McGuire M, Mitchell MC, Herlong HF, Veech GA, Veech RL (1990) Plasma tumor necrosis factor alpha predicts decreasing long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res 14:255–259
Feuerherm AJ, Borset M, Seidel C, Sundan A, Leistad L, Ostensen M, Faxvaag A (2001) Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. Scand J Rheumatol 30:229–234
Feyen JH, Elford P, Di Padova FE, Trechsel U (1989) Interleukin-6 is produced by bone and modulated by parathyroid hormone. J Bone Miner Res 4:633–638
Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA (1989) Increased plasma levels of interleukin-6 in sepsis. Blood 74:1704–1710
Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM (2001) Osteoprotegerin and receptor activator of nuclear factor κB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology (Oxford) 40:623–630
Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303
Kalabalikis P, Papazoglou K, Gouriotis D, Papadopoulos N, Kardara M, Papageorgiou F, Papadatos J (1999) Correlation between serum IL-6 and CRP levels and severity of head injury in children. Intensive Care Med 25:288–292
Khosla S, Arrighi HM, Melton LJ III, Atkinson EJ, O’Fallon WM, Dunstan C, Riggs BL (2002) Correlates of osteoprotegerin levels in women and men. Osteoporos Int 13:394–399
Kimble RB, Bain S, Pacifici R (1997) The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 12:935–941
Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, Gerstenfeld LC, Einhorn TA (2001) Expression of osteoprotegerin, receptor activator of NF-κB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 16:1004–1014
Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176
Masi L, Simonini G, Piscitelli E, DelMonte F, Giani T, Cimaz R, Vierucci S, Brandi ML, Falcini F (2004) Osteoprotegerin (OPG)/RANK-L system in juvenile idiopathic arthritis: is there a potential modulating role for OPG/RANK-L in bone injury? J Rheumatol 31:986–991
Ott L, McClain CJ, Gillespie M, Young B (1994) Cytokines and metabolic dysfunction after severe head injury. J Neurotrauma 11:447–472
Pacifici R (1996) Estrogen, cytokines and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 11:1043–1051
Perkins R, Skirving AP (1987) Callus formation and the rate of healing of femoral fractures in patients with head injuries. J Bone Joint Surg Br 69:521–524
Rogers A, Eastell R (2005) Circulating osteoprotegerin and receptor activator for nuclear factor κB Ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 90:6323–6331
Saidenberg-Kermanac’h N, Cohen-Solal M, Bessis N, De Vernejoul MC, Boissier MC (2004) Role for osteoprotegerin in rheumatoid inflammation. Joint Bone Spine 71:9–13
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319
Singhal A, Baker AJ, Hare GM (2002) Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury. J Neurotrauma 19:929–937
Spencer RF (1987) The effect of head injury on fracture healing: a quantitative assessment. J Bone Joint Surg Br 69:525–528
Stone MH, Newman RJ, Mukherjee SK (1987) Accelerated fracture union in association with severe head injury. Injury 18:241–246
Szalay F, Hegedus D, Lakatos PL, Tornai I, Bajnok E, Dunkel K, Lakatos P (2003) High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepatol 38:395–400
Taniguchi T, Koido Y, Aiboshi J, Yamashita T, Suzaki S, Kurokawa A (1999) The ratio of interleukin-6 to interleukin-10 correlated with severity in patients with chest and abdominal trauma. Am J Emerg Med 17:548–551
Trofilmov S, Pantsulaia I, Kobyliansky E, Livshits G (2004) Circulating levels of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin/macrophage-colony stimulating factor in a presumably healthy human population. Eur J Endocrinol 150:305–311
Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T (1989) The complex pattern of cytokines in serum from patients with meningococcal septic shock: association between interleukin-6, interleukin-1 and fatal outcome. J Exp Med 169:333–338
Waage A, Halstensen A, Espevik T (1987) Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1:355–357
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J. S. Lee and C. H. Ryu contributed equally to this study.
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Lee, J.S., Ryu, C.H., Moon, N.H. et al. Changes in serum levels of receptor activator of nuclear factor-κB ligand, osteoprotegerin, IL-6 and TNF-α in patients with a concomitant head injury and fracture. Arch Orthop Trauma Surg 129, 711–718 (2009). https://doi.org/10.1007/s00402-008-0632-8
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DOI: https://doi.org/10.1007/s00402-008-0632-8