Deneysel fare femur kaynamama modelinde lokal uygulanan simvastatinin etkileri

Yıl 2014, Cilt: 48 Sayı: 6, 679 - 684, 16.01.2015

Atilla Koçer Mithat Oner Ibrahim Karaman Derya Kocer Ibrahim Halil Kafadar Ahmet Guney Zehra Filiz Karaman

https://doi.org/10.3944/AOTT.2014.14.0120

Öz

Amaç: Bu çalışmanın amacı deneysel fare femur kaynamama modelinde lokal uygulanan simvastatinin etkilerini değerlendirmekti.

Çalışma planı: Bu çalışmada 32 Wistar albino fare kullanıldı. Fareler rastgele biçimde aşağıdaki 4 gruptan birine ayrıldı: iki kontrol grubu (kontrol-4 hafta [K4h] ve kontrol-8 hafta [K8h]) ve iki tedavi grubu (simvastatin-4 hafta [S4h] ve simvastatin-8 hafta [S8h]). Kontrol gruplarında cerrahi girişimden sonra 1 hafta süreyle dimetilsülfoksit (10 mg/kg/gün) lokal olarak enjekte edildi. Tedavi gruplarında ameliyat sonrası birinci günden itibaren 1 hafta boyunca simvastatinin sıvılaştırılmış formu (10 mg/kg/gün) lokal olarak osteotomi alanına enjekte edildi. K4h ve S4h gruplarındaki hayvanlar lokal tedavinin sonlanmasından 4 hafta, K8h ve S8h gruplarındaki hayvanlar ise 8 hafta sonra öldürüldü. Öldürülmeden önce biyokimyasal analiz için intrakardiyak kan örnekleri alındı ve radyografiler çekildi. Histopatolojik inceleme için farelerin sağ femurları çıkarıldı.

Bulgular: Radyolojik olarak incelendiğinde kontrol ve tedavi grupları arasında anlamlı farklılıklar mevcuttu. Tedavi gruplarında kontrol gruplarına kıyasla anlamlı şekilde daha yüksek kemiğe spesifik alkalin fosfataz ve osteokalsin değerleri saptandı.

Çıkarımlar: Biyokimyasal, radyolojik ve histopatolojik sonuçlara göre, fare femur kaynamama modelinde simvastatinin lokal uygulanması yararlı etkiler oluşturmaktadır.

Anahtar Kelimeler

Fare; femur; kaynamama; simvastatin

The effects of locally applied simvastatin on an experimental mouse femur nonunion model

Öz

Objective: The aim of this study was to assess the effects of locally applied simvastatin on femur nonunions in a mouse model.

Methods: The study included 32 male Wistar albino mice randomly allocated to one of four groups: two control groups (control-4 week [C4w] and control-8 week (C8w)] and two treatment groups (simvastatin-4 week [S4w] and simvastatin-8 week [S8w]). The control groups received dimethylsulfoxide locally injected at a dose of 10 mg/kg/day after surgical intervention for 1 week. Treatment groups received a liquefied form of simvastatin locally to the osteotomy field by injection at a dose of 10 mg/kg/day, starting from the first postoperative day for 1 week. The C4w and S4w groups were sacrificed 4 weeks and the C8w and S8w groups 8 weeks after the end of local treatment. Before sacrifice, intracardiac blood samples were retrieved for biochemical analysis and radiographies were taken. The right femurs of mice were then removed for histopathological evaluation.

Results: There were significant differences between the control and treatment groups when evaluated radiologically. Significantly higher levels of bone-specific alkaline phosphatase and osteocalcin values were found in the treatment groups than in the controls (p<0.05).

Conclusion: According to biochemical, radiological and histopathological results, local application of simvastatin appears to produce beneficial effects on the mouse femur nonunion model.

Anahtar Kelimeler

Femur, mouse, nonunion, simvastatin

Kaynakça

• Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res 1998;(355 Suppl):7-21.
• LaVelle DG. Delayed union and nonunion of fractures. In: Canale ST, editor. Campbell’s Operative Orthopae- dics. 10th ed. Philadelphia, PA: Mosby Publishers; 2003. p. 3126.
• Serin-Kilicoglu S, Erdemli E. New addition to the statin’s effect. J Trauma 2007;63:187-91.
• Human JA, Ubbink JB, Jerling JJ, Delport R, Vermaak WJ, Vorster HH, et al. The effect of Simvastatin on the plasma antioxidant concentrations in patients with hyper- cholesterolaemia. Clin Chim Acta 1997;263:67-77.
• Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Sim- vastatin inhibits the monocyte expression of proinflam- matory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 2000;36:427-31.
• van Nieuw Amerongen GP, Vermeer MA, Nègre-Aminou P, Lankelma J, Emeis JJ, van Hinsbergh VW. Simvastatin improves disturbed endothelial barrier function. Circula- tion 2000;102:2803-9.
• Gutierrez GE, Lalka D, Garrett IR, Rossini G, Mundy GR. Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concen- trations. Osteoporos Int 2006;17:1033-42.
• Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, et al. Stimulation of bone formation in vitro and in ro- dents by statins. Science 1999;286:1946-9.
• Price CP, Thompson PW. The role of biochemical tests in the screening and monitoring of osteoporosis. Ann Clin Biochem 1995;32:244-60.
• Lee AJ, Hodges S, Eastell R. Measurement of osteocalcin. Ann Clin Biochem 2000;37:432-46.
• Eastell R. Assessment of bone density and bone loss. Os- teoporos Int 1996;6 Suppl 2:3-5.
• Garcia P, Holstein JH, Maier S, Schaumlöffel H, Al-Mar- rawi F, Hannig M, et al. Development of a reliable non- union model in mice. J Surg Res 2008;147:84-91.
• Goldberg VM, Powell A, Shaffer JW, Zika J, Bos GD, Heiple KG. Bone grafting: role of histocompatibility in transplantation. J Orthop Res 1985;3:389-404.
• Huo MH, Troiano NW, Pelker RR, Gundberg CM, Fried- laender GE. The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histomorpho- metric parameters in rats. J Orthop Res 1991;9:383-90.
• Wang JW, Xu SW, Yang DS, Lv RK. Locally applied sim- vastatin promotes fracture healing in ovariectomized rat. Osteoporos Int 2007;18:1641-50.
• Skoglund B, Aspenberg P. Locally applied Simvastatin improves fracture healing in mice. BMC Musculoskelet Disord 2007;8:98.
• Fukui T, Ii M, Shoji T, Matsumoto T, Mifune Y, Kawaka- mi Y, et al. Therapeutic effect of local administration of low-dose simvastatin-conjugated gelatin hydrogel for frac- ture healing. J Bone Miner Res 2012;27:1118-31.
• Ayukawa Y, Yasukawa E, Moriyama Y, Ogino Y, Wada H, Atsuta I, et al. Local application of statin promotes bone repair through the suppression of osteoclasts and the enhancement of osteoblasts at bone-healing sites in rats. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:336-42.
• Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 2000;283:3211-6.
• Edwards CJ, Hart DJ, Spector TD. Oral statins and in- creased bone-mineral density in postmenopausal women. Lancet 2000;355:2218-9.
• Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, et al. Inhibitors of hydroxymethylglutaryl- coenzyme A reductase and risk of fracture among older women. Lancet 2000;355:2185-8.
• Chung YS, Lee MD, Lee SK, Kim HM, Fitzpatrick LA. HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients. J Clin Endocrinol Metab 2000;85:1137-42.
• Wada Y, Nakamura Y, Koshiyama H. Lack of positive cor- relation between statin use and bone mineral density in Japanese subjects with type 2 diabetes. Arch Intern Med 2000;160:2865.
• van Staa TP, Wegman S, de Vries F, Leufkens B, Coo- per C. Use of statins and risk of fractures. JAMA 2001;285:1850-5.
• LaCroix AZ, Cauley JA, Pettinger M, Hsia J, Bauer DC, McGowan J, et al. Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women’s Health Initiative Observational Study. Ann In- tern Med 2003;139:97-104.
• von Stechow D, Fish S, Yahalom D, Bab I, Chorev M, Müller R, et al. Does simvastatin stimulate bone forma- tion in vivo? BMC Musculoskelet Disord 2003;4:8.
• Garrett IR, Gutierrez GE, Rossini G, Nyman J, Mc- Cluskey B, Flores A, et al. Locally delivered lovastatin nanoparticles enhance fracture healing in rats. J Orthop Res 2007;25:1351-7.
• Rosenson RS, Tangney CC, Langman CB, Parker TS, Levine DM, Gordon BR. Short-term reduction in bone markers with high-dose simvastatin. Osteoporos Int 2005;16:1272-6.