EFFECTS OF SELECTIVE AND NON-SELECTIVE CYCLOOXYGENASE 2 INHIBITORS ON HETEROTOPIC OSSIFICATION IN RAT MODEL WITH Achilles TENOTOMY_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WUJiang ,  XIAOHaijun , XUEFeng , SHIWeizhe , ZHAOHang

Department of Orthopedics, the Third Clinical School of Southern Medical University, Fengxian Hospital Affiliated to Southern Medical University, Shanghai, 201400, P. R. China;

Corresponding?author：

XIAOHaijun, Email: xiaohaijun89@163.com

Keywords：

Heterotopic ossification; Selective cyclooxygenase 2 inhibitor; Non-selective cyclooxygenase 2 inhibitor; Rat

DOI：

10.7507/1002-1892.20140083

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Objective To compare the efficacy of selective cyclooxygenase 2 (COX2) inhibitor and non-selective COX2 inhibitor drugs in prevention of heterotopic ossification in rats model so as to provide reference for clinical drugs selection of heterotopic ossification prevention. Methods Fifty male Sprague Dawley rats, 6 to 8 weeks old, weight (190.0±8.5) g, were selected; the right Achilles tendon was cut off to induce ectopic bone formation. The rats were randomly divided into 5 groups (n=10):on the 1st day after modeling, celecoxib was given in groups A[2 mg/(kg·d)] and B[10 mg/(kg·d)], indomethacin in groups C[(2 mg/(kg·d) and D[10 mg/(kg·d)], and 2 mL of saline in group E for 10 weeks. The general condition of rats was observed after operation. At 5 and 10 weeks after operation, X-ray films of the right lower limb were taken to observe new bone formation. At 10 weeks after operation, the right Achilles tendon tissue was harvested for histological observation. Based on X-ray and histological results, heterotopic ossification was assessed. Immunohistochemical staining was used to evaluate COX2 and bone morphogenetic protein 2 (BMP-2) expression levels in local Achilles tendon. Results During the experiment, 5 rats died (2 in group B, 1 in group C, and 2 in group D), the other rats survived to the end of the experiment. General observation of Achilles tendon tissue showed that the tendon tissue volume of group B was the smallest, with soft texture and no cartilage-like tissue; the tendon tissue volume of group E was the biggest, with hard texture and cartilage-like tissue. The incidence of heterotopic ossification was 80.0% (8/10), 25.0% (2/8), 88.9% (8/9), 50.0% (4/8), and 100% (10/10) in groups A-E respectively at 10 weeks after operation; significant differences were found between groups B, D and group E (P=0.002,P=0.023) and between groups B and C (P=0.015), but no significant difference was found among the other groups (P>0.05). COX2 expression level in groups B and D was significantly lower than that in group E (P<0.05), but no significant difference was found among the other groups (P>0.05); BMP-2 expression level in group B was significantly lower than that in groups A, C, and E (P<0.05), but no significant difference was found among the other groups (P>0.05). Conclusion Celecoxib at a dose of 10 mg/(kg·d) can effectively reduce the incidence of heterotopic ossification in rats.

Citation： WUJiang, XIAOHaijun, XUEFeng, SHIWeizhe, ZHAOHang. EFFECTS OF SELECTIVE AND NON-SELECTIVE CYCLOOXYGENASE 2 INHIBITORS ON HETEROTOPIC OSSIFICATION IN RAT MODEL WITH Achilles TENOTOMY. Chinese Journal of Reparative and Reconstructive Surgery, 2014, 28(3): 371-376. doi: 10.7507/1002-1892.20140083 Copy

1.	Pakos EE, Stafilas KS, Tsekeris PG, et al. Combined radiotherapy and indomethacin for the prevention of heterotopic ossification after total hip arthroplasty. Strahlenther Onkol, 2009, 185(8):500-505.
2.	Le Duff MJ, Takamura KB, Amstutz HC. Incidence of heterotopic ossification and effects of various prophylactic methods after hip resurfacing. Bull NYU Hosp Jt Dis, 2011, 69(Suppl 1):S36-S41.
3.	Xu JC, Wu T, Wu GH, et al. Leptin expression by heterotopic ossification-isolated tissue in rats with Achilles' tenotomy. Saudi Med J, 2009, 30(5):605-610.
4.	徐俊昌, 吳濤, 吳桂華, 等. 跟腱切斷法誘導大鼠異位骨化動物模型的建立. 中國矯形外科雜志, 2009, 17(8):625-627.
5.	Zhang K, Wang L, Zhang S, et al. Celecoxib inhibits the heterotopic ossification in the rat model with Achilles tenotomy. Eur J Orthop Surg Traumatol, 2013, 23(2):145-148.
6.	Ma Y, Ma L, Guo Q, et al. Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients. J Exp Clin Cancer Res, 2010, 29:85.
7.	Zhu H, Zhou X, Redfield S, et al. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. Am J Transl Res, 2013, 5(3):368-378.
8.	Lin L, Shen Q, Xue T, et al. Heterotopic ossification induced by Achilles tenotomy via endochondral bone formation:expression of bone and cartilage related genes. Bone, 2010, 46(2):425-431.
9.	FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med, 2001, 345(6):433-442.
10.	Jouzeau JY, Terlain B, Abid A, et al. Cyclo-oxygenase isoenzymes. How recent findings affect thinking about nonsteroidal anti-inflamatory drugs. Drugs, 1997, 53(4):563-582.
11.	Wittenberg RH, Peschke U, B?tel U. Heterotopic ossification after spinal cord injury. Epidemiology and risk factor. J Bone Joint Surg (Br), 1992, 74(2):215-218.
12.	毛玉江, 王滿宜, 呂厚山. 吲哚美辛干預家兔髖關節異位成骨的實驗觀察. 中華創傷骨科雜志, 2005, 7(5):447-451.
13.	Murat N, Hocaoglu N, Karatosun V, et al. The effects of non-selective and cyclooxygenase-2-selective non-steroidal anti-inflammatory drugs on heterotopic ossification in rats. Med Sci Monit, 2005, 11(12):BR449-451.
14.	Rapuano BE, Boursiquot R, Tomin E, et al. The effects of COX-1 and COX-2 inhibitors on prostaglandin synthesis and the formation of heterotopic bone in a rat model. Arch Orthop Trauma Surg, 2008, 128(3):333-344.
15.	Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone:bad cop, good cop? Trends Endocrinol Metab, 2010, 21(5):294-301.
16.	Toom A, Arend A, Gunnarsson D, et al. Bone formation zones in heterotopic ossifications:histologic findings and increased expression of bone morphogenetic protein 2 and transforming growth factors beta2 and beta3. Calcif Tissue Int, 2007, 80(4):259-267.
17.	Macfarlane RJ, Ng BH, Gamie Z, et al. Pharmacological treatment of heterotopic ossification following hip and acetabular surgery. Expert Opin Pharmacother, 2008, 9(5):767-786.
18.	Günal I, Hazer B, Seber S, et al. Prevention of heterotopic ossification after total hip replacement:a prospective comparison of indomethacin and salmon calcitonin in 60 patients. Acta Orthop Scand, 2001, 72(5):467-469.
19.	Knelles D, Barthel T, Karrer A, et al. Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation. J Bone Joint Surg (Br), 1997, 79(4):596-602.
20.	Barbato M, D'Angelo E, Di Loreto G, et al. Adherence to routine use of pharmacological prophylaxis of heterotopic ossification after total hip arthroplasty:results from an Italian multicenter, prospective, observational survey. J Orthop Traumatol, 2012, 13(2):63-67.

1. Pakos EE, Stafilas KS, Tsekeris PG, et al. Combined radiotherapy and indomethacin for the prevention of heterotopic ossification after total hip arthroplasty. Strahlenther Onkol, 2009, 185(8):500-505.
2. Le Duff MJ, Takamura KB, Amstutz HC. Incidence of heterotopic ossification and effects of various prophylactic methods after hip resurfacing. Bull NYU Hosp Jt Dis, 2011, 69(Suppl 1):S36-S41.
3. Xu JC, Wu T, Wu GH, et al. Leptin expression by heterotopic ossification-isolated tissue in rats with Achilles' tenotomy. Saudi Med J, 2009, 30(5):605-610.
4. 徐俊昌, 吳濤, 吳桂華, 等. 跟腱切斷法誘導大鼠異位骨化動物模型的建立. 中國矯形外科雜志, 2009, 17(8):625-627.
5. Zhang K, Wang L, Zhang S, et al. Celecoxib inhibits the heterotopic ossification in the rat model with Achilles tenotomy. Eur J Orthop Surg Traumatol, 2013, 23(2):145-148.
6. Ma Y, Ma L, Guo Q, et al. Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients. J Exp Clin Cancer Res, 2010, 29:85.
7. Zhu H, Zhou X, Redfield S, et al. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. Am J Transl Res, 2013, 5(3):368-378.
8. Lin L, Shen Q, Xue T, et al. Heterotopic ossification induced by Achilles tenotomy via endochondral bone formation:expression of bone and cartilage related genes. Bone, 2010, 46(2):425-431.
9. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med, 2001, 345(6):433-442.
10. Jouzeau JY, Terlain B, Abid A, et al. Cyclo-oxygenase isoenzymes. How recent findings affect thinking about nonsteroidal anti-inflamatory drugs. Drugs, 1997, 53(4):563-582.
11. Wittenberg RH, Peschke U, B?tel U. Heterotopic ossification after spinal cord injury. Epidemiology and risk factor. J Bone Joint Surg (Br), 1992, 74(2):215-218.
12. 毛玉江, 王滿宜, 呂厚山. 吲哚美辛干預家兔髖關節異位成骨的實驗觀察. 中華創傷骨科雜志, 2005, 7(5):447-451.
13. Murat N, Hocaoglu N, Karatosun V, et al. The effects of non-selective and cyclooxygenase-2-selective non-steroidal anti-inflammatory drugs on heterotopic ossification in rats. Med Sci Monit, 2005, 11(12):BR449-451.
14. Rapuano BE, Boursiquot R, Tomin E, et al. The effects of COX-1 and COX-2 inhibitors on prostaglandin synthesis and the formation of heterotopic bone in a rat model. Arch Orthop Trauma Surg, 2008, 128(3):333-344.
15. Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone:bad cop, good cop? Trends Endocrinol Metab, 2010, 21(5):294-301.
16. Toom A, Arend A, Gunnarsson D, et al. Bone formation zones in heterotopic ossifications:histologic findings and increased expression of bone morphogenetic protein 2 and transforming growth factors beta2 and beta3. Calcif Tissue Int, 2007, 80(4):259-267.
17. Macfarlane RJ, Ng BH, Gamie Z, et al. Pharmacological treatment of heterotopic ossification following hip and acetabular surgery. Expert Opin Pharmacother, 2008, 9(5):767-786.
18. Günal I, Hazer B, Seber S, et al. Prevention of heterotopic ossification after total hip replacement:a prospective comparison of indomethacin and salmon calcitonin in 60 patients. Acta Orthop Scand, 2001, 72(5):467-469.
19. Knelles D, Barthel T, Karrer A, et al. Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation. J Bone Joint Surg (Br), 1997, 79(4):596-602.
20. Barbato M, D'Angelo E, Di Loreto G, et al. Adherence to routine use of pharmacological prophylaxis of heterotopic ossification after total hip arthroplasty:results from an Italian multicenter, prospective, observational survey. J Orthop Traumatol, 2012, 13(2):63-67.

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Chinese Journal of Reparative and Reconstructive Surgery

EFFECTS OF SELECTIVE AND NON-SELECTIVE CYCLOOXYGENASE 2 INHIBITORS ON HETEROTOPIC OSSIFICATION IN RAT MODEL WITH Achilles TENOTOMY

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