The effect of HIF stabilizer on distraction osteogenesis

Yıl 2015, Cilt: 49 Sayı: 1, 80 - 84, 19.03.2015

Ahmet Ozdel Bartu Sarisozen Ulviye Yalcinkaya Burak Demirag

https://doi.org/10.3944/AOTT.2015.14.0006

Öz

Objective: The aim of this study was to investigate the effect of an orally applicable hypoxia-inducible factor (HIF) stabilizer on distraction osteogenesis (DO) in a rat model.

Methods: The study included 24 Wistar albino rats undergoing osteotomy of the left tibia diaphysis. Rats were divided equally into experiment and control groups. Tibias were fixed using an external fixator. HIF stabilizer was administered to the experiment group. On the 5th postoperative day, distraction with increased rate (0.4 mm twice a day) was commenced and continued for 10 days. Histological and immunohistochemical evaluation was performed.

Results: Vascular endothelial growth factor levels of the experiment group were higher than those of the control group (p<0.05). The experiment group had slightly better intramembranous ossification quality than the control group on both Day 16 and 30. Endochondral ossification rates were better in the experiment group on Day 16.

Conclusion: Vascular endothelial growth factor levels increased and stimulated angiogenesis in the presence of HIF pathway activation by oral administration of HIF stabilizer during DO. The biomechanical features of the distraction and angiogenesis should be coupled to achieve adequate bone homeostasis.

Anahtar Kelimeler

Angiogenesis, distraction osteogenesis, HIF stabilizer, VEGF

Distraksiyon osteogenezinde HİFstabilizasyonunun etkisi

Öz

Amaç: Çalışmamızda sıçandaki distraksiyon osteogenezi (DO) modelinde oral olarak uygulanabilen hipoksi ile indüklenebilir faktörün (HİF) etkisinin incelemeyi amaçladık.

Çalışma planı: Çalışmada sol tibia diyafizine osteotomi uygulanan 24 Wistar albino sıçan kullanıldı. Denekler deney ve kontrol olmak üzere iki gruba ayrıldı. Eksternal fiksatör ile tespit sağlanarak, deney grubuna HİF stabilizatörü verildi. Cerrahi sonrası 5. günlük latent dönemi takiben, 10 gün boyunca hızlandırılmış distraksiyon (günde iki kez 0.4 mm) uygulandı. Histolojik ve immünohistokimyasal değerlendirmeler yapıldı.

Bulgular: Deney grubundaki vasküler endotelial büyüme faktörü (VEBF) düzeyi kontrol grubuna kıyasla daha yüksek idi (p<0.05). Deney grubundaki intramembranöz ossifikasyon oranının 16. ve 30. günlerde kontrol grubuna göre bir miktar daha yüksek olduğu gözlendi. Yine deney grubundaki endokondral ossifikasyon miktarının 16. günde daha yüksek olduğu bulundu.

Çıkarımlar: Hipoksi ile indüklenebilir faktör stabilizatörünün oral olarak uygulanması ile DO sıra¬sında VEBF düzeylerinin yükselerek HİF yolağının aktive olması sonucu anjiyogenezin uyarıldığını gösterdik. İyi bir kemik oluşumu için distraksiyona ait biyomekanik faktörler ve anjiyogenezin eşleş¬mesi gereklidir.

Anahtar Kelimeler

Anjiyogenez; distraksiyon osteogenezi; HİF stabilizatörü; VEBF.

Kaynakça

• Trueta J, Trıas A. The vascular contribution to osteogene- sis. IV. The effect of pressure upon the epiphysial cartilage of the rabbit. J Bone Joint Surg Br 1961;43:800-13.
• Trueta J, Buhr Aj. The Vascular Contrıbutıon To Osteogenesıs. V. The Vasculature Supplyıng The Epıphysıal Cartılage In Rachıtıc Rats. J Bone Joint Surg Br 1963;45:572-81.
• 3 Risau W. Mechanisms of angiogenesis. Nature 1997;386:671-4.
• Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9:685-93.
• Huddleston PM, Steckelberg JM, Hanssen AD, Rouse MS, Bolander ME, Patel R. Ciprofloxacin inhibition of experimental fracture healing. J Bone Joint Surg Am 2000;82:161-73.
• Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Günzler V, et al. Inhibition of prolyl hy- droxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010;21:2151-6.
• Philipp S, Jürgensen JS, Fielitz J, Bernhardt WM, Weide- mann A, Schiche A, et al. Stabilization of hypoxia induc- ible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarc- tion in rats. Eur J Heart Fail 2006;8:347-54.
• Ma TC, Langley B, Ko B, Wei N, Gazaryan IG, Zareen N, et al. A screen for inducers of p21(waf1/cip1) identi- fies HIF prolyl hydroxylase inhibitors as neuroprotec- tive agents with antitumor properties. Neurobiol Dis 2013;49:13-21.
• Little DG, Cornell MS, Briody J, Cowell CT, Arbuckle S, Cooke-Yarborough CM. Intravenous pamidronate reduc- es osteoporosis and improves formation of the regenerate during distraction osteogenesis. A study in immature rab- bits. J Bone Joint Surg Br 2001;83:1069-74.
• Okazaki H, Kurokawa T, Nakamura K, Matsushita T, Ma- mada K, Kawaguchi H. Stimulation of bone formation by recombinant fibroblast growth factor-2 in callotasis bone lengthening of rabbits. Calcif Tissue Int 1999;64:542-6.
• Raschke MJ, Bail H, Windhagen HJ, Kolbeck SF, Weiler A, Raun K, et al. Recombinant growth hormone acceler- ates bone regenerate consolidation in distraction osteo- genesis. Bone 1999;24:81-8.
• Stewart KJ, Weyand B, van’t Hof RJ, White SA, Lvoff GO, Maffulli N, et al. A quantitative analysis of the ef- fect of insulin-like growth factor-1 infusion during man- dibular distraction osteogenesis in rabbits. Br J Plast Surg 1999;52:343-50.
• Williams PR, Smith NC, Cooke-Yarborough C, Little DG. Bisphosphonates and nephrocalcinosis in a rabbit leg lengthening model: a histological and therapeutic compar- ison. Pharmacol Toxicol 2001;89:149-52.
• Yamane K, Okano T, Kishimoto H, Hagino H. Effect of ED-71 on modeling of bone in distraction osteogenesis. Bone 1999;24:187-93.
• Tsubota S, Tsuchiya H, Shinokawa Y, Tomita K, Minato H. Transplantation of osteoblast-like cells to the distract- ed callus in rabbits. J Bone Joint Surg Br 1999;81:125-9.
• Wan C, Gilbert SR, Wang Y, Cao X, Shen X, Ramaswamy G, et al. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A 2008;105:686-91.
• Fassbender M, Strobel C, Rauhe JS, Bergmann C, Schmidmaier G, Wildemann B. Local inhibition of angio- genesis results in an atrophic non-union in a rat osteotomy model. Eur Cell Mater 2011;22:1-11.
• Ji B, Jiang G, Fu J, Long J, Wang H. Why high frequency of distraction improved the bone formation in distraction osteogenesis? Med Hypotheses 2010;74:871-3.
• Paccione MF, Mehrara BJ, Warren SM, Greenwald JA, Spector JA, Luchs JS, et al. Rat mandibular distraction os- teogenesis: latency, rate, and rhythm determine the adap- tive response. J Craniofac Surg 2001;12:175-82.
• Djasim UM, Mathot BJ, Wolvius EB, van Neck JW, van der Wal KG. Histomorphometric comparison between continuous and discontinuous distraction osteogenesis. J Craniomaxillofac Surg 2009;37:398-404.
• Aronson J, Shen XC, Skinner RA, Hogue WR, Badger TM, Lumpkin CK Jr. Rat model of distraction osteogen- esis. J Orthop Res 1997;15:221-6.
• Aronson J. Experimental and clinical experience with distraction osteogenesis. Cleft Palate Craniofac J 1994;31:473-82.
• Li G, Simpson AH, Kenwright J, Triffitt JT. Assessment of cell proliferation in regenerating bone during distrac- tion osteogenesis at different distraction rates. J Orthop Res 1997;15:765-72.