Advertisement

Journal of Molecular Histology

, Volume 44, Issue 6, pp 723–731 | Cite as

Cyclooxygenase-2 inhibition does not impair block bone grafts healing in rabbit model

  • Eduardo Moreschi
  • Claudia Cristina Biguetti
  • Eliston Comparim
  • Leandro De Andrade Holgado
  • Paulo Domingos Ribeiro-Junior
  • Hugo Nary-Filho
  • Mariza Akemi Matsumoto
Original Paper

Abstract

Success of alveolar reconstructions using onlay autogenous block bone grafts depends on their adequate integration to the recipient bed influenced by a number of local molecules. Considering the fundamental role of cyclooxygenase (COX-2) in bone repair, the aim of this study was to analyze the effect of its inhibition in the integration of endochondral (EC) iliac crest, and intramembranous (IM) calvaria bone grafts. Thirty-two rabbits were divided into 4 groups: Calvaria Control (CC) and Iliac Control—treated with oral 0.9 % saline solution, and Calvarial-NSAID (C-NSAID) and Iliac-NSAID (I-NSAID) groups—treated with oral 6 mg/Kg non-steroidal anti-inflammatory drug etoricoxib. After 7, 14, 30 and 60 days the animals were euthanized and the specimens removed for histological, histomorphometric and immunohistochemistry analysis. At day 60, a tight integration of IM blocks could be seen with the presence of remodeling bone, whereas integration of EC grafts was mainly observed at the edges of the grafts. A significant higher percentage of bone matrix in the interface region of the CC grafts in comparison to C-NSAID only at day 14, whereas no differences were detected comparing the EC grafts. No differences were observed in Runx-2 and vascular endothelial growth factor (VEGF) immunolabeling when comparing CC and C-NSAID groups, while a significant weaker Runx-2 and VEGF labeling was detected in I-NSAID group at day 60. Although some influence was detected in osteogenesis, it is concluded that drug induced inhibition of COX-2 does not impair onlay bone grafts’ healing of both embryologic origins in rabbits.

Keywords

COX-2 Autogenous bone grafts Immunohistochemistry Cbfa1/Runx-2 VEGF 

Notes

Acknowledgments

The authors are grateful to Maira Cristina Rondina Couto for histology and immunohistochemistry assistance. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant Numbers 2008/11485-7, 2009/14989-9).

References

  1. Aghaloo TL, Moy PK (2007) Which hard tissue augmentation techniques are the most successful in furnishing bony support for implant placement? Int J Oral Maxillofac Implants 22(Suppl):49–70PubMedGoogle Scholar
  2. Biguetti CC, Filho EJ, de Andrade Holgado L, Caviquioli G, Moreschi E, Comparin E, Matsumoto MA (2012) Effect of low-level laser therapy on intramembranous and endochondral autogenous bone grafts healing. Microsc Res Tech 75:1237–1244PubMedCrossRefGoogle Scholar
  3. Brown KM, Saunders MM, Kirsch T, Donahue HJ, Reid JS (2004) Effect of COX-2 specific inhibition on fracture healing in the rat femur. J Bone Joint Surg Am 86A:116–123Google Scholar
  4. Carano RA, Filvaroff EH (2003) Angiogenesis and bone repair. Drug Discov Today 8:980–989PubMedCrossRefGoogle Scholar
  5. Chen Q, Rho JY, Fan Z, Laulederkind SJF, Raghow R (2003) Congenital lack of COX-2 affects mechanical and geometric properties of bone in mice. Calcif Tissue Int 73:387–392PubMedCrossRefGoogle Scholar
  6. Chikazu D, Fujikawa Y, Fujihara H, Suenaga H, Saijo H, Ohkubo K, Ogasawara T, Mori Y, Iino M, Takato T (2011) Cyclooxygenase-2 activity is important in craniofacial fracture repair. Int J Oral Maxillofac Surg 40:322–326PubMedCrossRefGoogle Scholar
  7. Cottrell J, O’Connor PJ (2010) Effect of non-steroidal anti-inflammatory drugs on bone healing. Pharmaceuticals 3:1668–1693CrossRefGoogle Scholar
  8. Einhorn TA (2002) Do inhibitors of cyclooxygenase-2 impair bone healing? J Bone Miner Res 17:977–978PubMedCrossRefGoogle Scholar
  9. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA (2003) Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res 21:670–675PubMedCrossRefGoogle Scholar
  10. Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, Verburg KM, Geis GS (2000) Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 95:1681–1690PubMedCrossRefGoogle Scholar
  11. Greenberg JA, Wiltz MJ, Kraut RA (2012) Augmentation of the anterior maxilla with intraoral onlay grafts for implant placement. Implant Dent 21:21–24PubMedCrossRefGoogle Scholar
  12. Hak DJ, Schulz KS, Khoie B, Hazelwood SJ (2011) The effect of Cox-2 specific inhibition on direct fracture healing in the rabbit tibia. J Orthop Sci 16(1):93–98PubMedCrossRefGoogle Scholar
  13. Harada S (1994) Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest 93:2490–2496PubMedCrossRefGoogle Scholar
  14. Kanczler JM, Oreffo RO (2008) Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater 2(15):100–114Google Scholar
  15. Kusiak JF, Zins JE, Whitaker LA (1985) The early revascularization of membranous bone. Plast Reconstr Surg 76:510–514PubMedCrossRefGoogle Scholar
  16. Lau KH, Kothari V, Das A, Zhang XB, Baylink DJ (2013) Cellular and molecular mechanisms of accelerated fracture healing by COX2 gene therapy: studies in a mouse model of multiple fractures. Bone 53:369–381PubMedCrossRefGoogle Scholar
  17. Matsumoto MA, Oliveira A, Ribeiro P Jr, Nary Filho H, Ribeiro DA (2008) Short-term administration of non-selective and selective Cox-2 NSAIDS do not interfere with bone repair in rats. J Mol Histol 39(4):381–387PubMedCrossRefGoogle Scholar
  18. Miranda SR, Nary Filho H, Padovan LEM, Nicolielo D, Matsumoto MA (2006) Use of platelet-rich plasma under autogenous onlay bone grafts. Clin Oral Implant Res 17(694):699Google Scholar
  19. Misch CM (2011) Maxillary autogenous bone grafting. Oral Maxillofac Surg Clin North Am 23:229–238PubMedCrossRefGoogle Scholar
  20. Mullis BH, Copland ST, Weinhold PS, Miclau T, Lester GE, Bos GD (2006) Effect of COX-2 inhibitors and non-steroidal anti-inflammatory drugs on a mouse fracture model. Injury 37:827–837PubMedCrossRefGoogle Scholar
  21. Needelman P, Isakson PC (1997) The discovery and function of COX-2. J Rheumatol 24(Suppl 49):6–8Google Scholar
  22. O’Keefe RJ, Tivapatanaputti P, Xie C, Li TF, Clark C, Zuscik MJ (2006) COX-2 has acritical role during incorporation of structural bone allografts. Ann N Y Acad Sci 1068:532–542PubMedCrossRefGoogle Scholar
  23. Pedrosa WF Jr, Okamoto R, Faria PE, Arnez MF, Xavier SP, Salata LA (2009) Immunohistochemical, tomographic and histological study on onlay bone graft remodeling. Part II: calvarial bone. Clin Oral Implant Res 20(11):1254–1264CrossRefGoogle Scholar
  24. Sato Y, Arai N, Negishi A, Ohya K (1997) Expression of cyclooxygenase genes and involvement of endogenous prostaglandin during osteogenesis in the rat tibial bone marrow cavity. J Med Dent Sci 44:81–92PubMedGoogle Scholar
  25. Scott CK, Hightower JA (1991) The matrix of endochondral bone differs from the matrix of intramembranous bone. Calcif Tissue Int 49:349–354PubMedCrossRefGoogle Scholar
  26. Simon AM, Manigrasso MB, O’connor JP (2002) Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 17:963–976PubMedCrossRefGoogle Scholar
  27. Street J, Bao M, deGuzman L, Bunting S, Peale FV Jr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA 23(99):9656–9661CrossRefGoogle Scholar
  28. Sullivan WG, Szwajkun PR (1991) Revascularization of cranial versus iliac crest bone grafts in the rat. Plast Reconstr Surg 87:1105–1109PubMedCrossRefGoogle Scholar
  29. Suttapreyasri S, Koontongkaew S, Phongdara U, Leggat U (2006) Expression of bone morphogenetic proteins in normal human intramembranous and endochondral bones. Int J Oral Maxillofac Surg 35:444–452PubMedCrossRefGoogle Scholar
  30. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K (2000) 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem 43:775–777PubMedCrossRefGoogle Scholar
  31. Twitty A, Rabie AB, Shum DK, Wong RW, Cheung LK (2006) Expression of tissue inhibitor of metalloproteinase during early stages of bone graft healing. Front Biosci 11:1861–1869PubMedCrossRefGoogle Scholar
  32. Vaes BL, Ducy P, Sijbers AM, Hendriks JM, van Someren EP, de Jong NG, van den Heuvel ER, Olijve W, van Zoelen EJ, Dechering KJ (2006) Microarray analysis on Runx2-deficient mouse embryos reveals novel Runx2 functions and target genes during intramembranous and endochondral bone formation. Bone 39:724–738PubMedCrossRefGoogle Scholar
  33. Zhang X, Schwarz EM, Young DA, Puzas E, Rosier RN, O’keefe RJ (2002) Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 109:1405–1415PubMedGoogle Scholar
  34. Zins JE, Whitaker LA (1983) Membranous versus endochondral bone: implications for craniofacial reconstruction. Plast Reconstr Surg 72:778–785PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Eduardo Moreschi
    • 1
    • 2
  • Claudia Cristina Biguetti
    • 3
  • Eliston Comparim
    • 1
  • Leandro De Andrade Holgado
    • 4
  • Paulo Domingos Ribeiro-Junior
    • 4
  • Hugo Nary-Filho
    • 4
    • 5
  • Mariza Akemi Matsumoto
    • 4
  1. 1.Oral and Maxillofacial Surgery Doctoral’s Course ProgramSagrado Coração University (USC)BauruBrazil
  2. 2.Centro Universitário de Maringá (CESUMAR)MaringáBrazil
  3. 3.Oral Biology Master’s Course Program, Department of Biological Sciences, Bauru School of DentistrySão Paulo University, FOB/USPBauruBrazil
  4. 4.Department of Health SciencesSagrado Coração University (USC)BauruBrazil
  5. 5.PI Branemark Institute BauruBauruBrazil

Personalised recommendations