J Korean Fract Soc.  2008 Apr;21(2):145-150. 10.12671/jkfs.2008.21.2.145.

Alterations in Serum Levels of Receptor Activator of Nuclear Factor-kappa B Ligand and Osteoprotegerin in Patients with Head Injury and Fracture

• Park SY
• Suh KT
• Ryu CH
• Woo SH
• Lee JS
• Kim SG

• KMID: 2183911
• DOI: http://doi.org/10.12671/jkfs.2008.21.2.145

Abstract

PURPOSE: Receptor activator of nuclear factor-kappa B ligand (RANKL), 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 and OPG in patients with head injury and fracture are lacking. We evaluated the changes in serum levels of RANKL and OPG in patients with head injury and fracture (head injury group) and in patients with fracture (fracture group) and compared these with levels found in healthy control subjects.
MATERIALS AND METHODS
18 male patients of head injury and fracture and 20 male patients of fracture alone were enrolled. 20 healthy men were recruited to serve as controls. Within the first few hours of admission to hospital, at 4, 8 and 12 weeks after injury 20 ml of blood were obtained from 18 patients with head injury and fracture and 20 patients with fracture only.
RESULTS
RANKL levels were significantly lower in the head injury group than in the fracture group at 8 and 12 weeks after injury. OPG levels were significantly higher in the head injury group than in the fracture group at 4, 8 and 12 weeks after injury. RANKL/OPG ratios were significantly lower in the head injury group than in the controls immediately after and 4, 8 and 12 weeks after injury, and were significantly lower in the head injury group than in the fracture group at 8 and 12 weeks after injury.
CONCLUSION
We have shown changes in the profiles of RANKL, OPG and RANKL to OPG ratio. The altered RANKL, OPG and RANKL/OPG ratio in the head injury group lasted longer than in those of the fracture group.

Keyword

Head injury; Fracture; RANKL; OPG

MeSH Terms

Animals
Bone Remodeling
Craniocerebral Trauma
Fracture Healing
Head
Humans
Male
Mice
Osteoprotegerin
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Tibial Fractures
Osteoprotegerin
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B

Figure

• 

  Fig. 1 The RANKL levels of the three groups were expressed in terms of the pg/ml immediately after injury, 4, 8 and 12 weeks after injury (statistically significant difference, *; Head injury and fracture group and control group, **; Fracture group and control group, ***; Head injury and fracture group and Fracture group).

• 

  Fig. 2 The OPG levels of the three group were expressed in terms of the pg/mL immediately after injury, 4, 8 and 12 weeks after injury (statistically significant difference, *; Head injury and fracture group and control group, **; Fracture group and control group, ***; Head injury and fracture group and Fracture group).

• 

  Fig. 3 The RANKL/OPG levels of the three groups were showed immediately after injury, 4, 8 and 12 weeks after injury (statistically significant difference, *; Head injury and fracture group and control group, **; Fracture group and control group, ***; Head injury and fracture group and Fracture group).

Reference

1. Beeton CA, Charfield D, Brooks RA, Rushton N. Circulating levels of interleukin-6 and its soluble receptor in patients with head injury and fracture. J Bone Joint Surg Br. 2004; 86:912–917.

2. Bidner SM, Rubins IM, Desjardins JV, Zukor DJ, Goltzman D. Evidence for a humoral mechanism for enhanced osteogenesis after head injury. J Bone Joint Surg Am. 1990; 72:1144–1149.

3. Boes M, Kain M, Kakar S, et al. Ostoegenic effects of traumatic brain injury on experimental fracture-healing. J Bone Joint Surg Am. 2006; 88:738–743.

4. Einhorn TA, Majeska RJ, Rush EB, Levine PM, Horowitz MC. The expression of cytokine activity by fracture callus. J Bone Miner Res. 1995; 10:1272–1281.

5. Felver ME, Mezey E, McGuire M, et al. Plasma tumor necrosis factor alpha predicts decreasing long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res. 1990; 14:255–259.

6. Feuerherm AJ, Borset M, Seidel C, et al. Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. Scand J Rheumatol. 2001; 30:229–234.

7. Garland DE, Rothi B, Waters RL. Femoral fractures in head injured adults. Clin Orthop Relat Res. 1982; 166:219–225.

8. Garland DE, Toder L. Fractures of the tibial diaphysis in adults with head injuries. Clin Orthop Relat Res. 1980; 150:198–202.

9. Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology (Oxford). 2001; 40:623–630.

10. Kalabalikis P, Papazogbou K, Gouriotis D, et al. Correlation between serum IL-6 and CRP levels and severity of head injury in children. Intensive Care Med. 1999; 25:288–292.

11. Khosla S, Arrighi HM, Melton LJ 3rd, et al. Correlates of osteoprotegerin levels in women and men. Osteoporos Int. 2002; 13:394–399.

12. Kimble RB, Bain S, Pacifici R. The functional block of TNF but not IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res. 1997; 12:935–941.

13. Kon T, Cho TJ, Aizawa T, et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res. 2001; 16:1004–1014.

14. Kurer MH, Khoker MA, Dandona P. Human osteoblast stimulation by sera from paraplegic patients with heterotopic ossification. Paraplegia. 1992; 30:165–168.

15. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998; 93:165–176.

16. Newman RJ, Stone MH, Mukherjee SK. Accelerated fracture union in association with severe head injury. Injury. 1987; 18:241–246.

17. Ott L, McClain CJ, Gillespie M, Young B. Cytokines and metabolic dysfunction after severe head injury. J Neurotrauma. 1994; 11:447–472.

18. Perkins R, Skirving AP. Callus formation and the rate of healing of femoral fractures in patients with head injuries. J Bone Joint Surg Br. 1987; 69:521–524.

19. Renfree KJ, Banovac K, Hornicek FJ, Lebowohl NH, Villanueva PA, Nedd KJ. Evaluation of serum osteoblast mitogenic activity in spinal cord and head injury patients with acute heterotopic ossification. Spine. 1994; 19:740–746.

20. Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor Kappa B ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab. 2005; 90:6323–6331.

21. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89:309–319.

22. Singhal A, Baker AJ, Hare GM, Reinders FX, Schlichter LC, Moulton RJ. Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury. J Neurotrauma. 2002; 19:929–937.

23. Sohn HM, Ha SH, Lee JY, Lee YK. Delayed operative treatment of long bone fractures in patients with brain injury. J Korean Fract Soc. 2006; 19:157–162.

24. Spencer RF. The effect of head injury on fracture healing. A quantitative assessment. J Bone Joint Surg Br. 1987; 69:525–528.

25. Szalay F, Hegedus D, Lakatos PL, et al. High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepatol. 2003; 38:395–400.

26. Trofimov S, Pantsulaia I, Kobyliansky E, Livshits G. Circulating levels of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin/macrophage-colony stimulating factor in a presumably healthy human population. Eur J Endocrinol. 2004; 150:305–311.

27. Tsur A, Sazbon L, Lotem M. Relationship between muscular tone, movement and periarticular new bone formation in postcoma-unaware (PC-U) patients. Brain Inj. 1996; 10:259–262.

28. Wildburger R, Zarkovic N, Egger G, Petek W, Zarkovic K, Hofer HP. Basic fibroblast growth factor (BFGF) immunoreactivity as a possible link between head injury and impaired bone fracture healing. Bone Miner. 1994; 27:183–192.

29. Wildburger R, Zarkovic N, Tonkovic G, et al. Post-traumatic hormonal disturbances: prolactin as a link between head injury and enhanced osteogenesis. J Endocrinol Invest. 1998; 21:78–86.

30. Yang KH, Choi CH, Cho JH. Stimulation of fracture healing by low-intensity pulsing ultrasound. J Korean Soc Fract. 1998; 11:247–253.