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Upregulation of VEGF in Subchondral Bone of Necrotic Femoral Heads in Rabbits with Use of Extracorporeal Shock Waves

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Abstract

Extracorporeal shock wave treatment appears to be effective in patients with avascular necrosis of the femoral head. However, the pathway of biological events whereby this is accomplished has not been fully elucidated. The purpose of this study was to investigate the effect of extracorporeal shock waves on vascular endothelial growth factor (VEGF) expression in necrotic femoral heads of rabbits. VEGF expression was assessed by immunohistochemistry, quantitative real-time PCR, and Western blot analysis. The degree of angiogenesis was also assessed, as determined by the microvessel density (MVD), the assessment of which was based on CD31-expressing vessels. Bilateral avascular necrosis of femoral heads was induced with methylprednisolone and lipopolysaccharide in 30 New Zealand rabbits. The left limb (the study side) received shock wave therapy to the femoral head. The right limb (the control side) received no shock wave therapy. Biopsies of the femoral heads were performed at 1, 2, 4, 8, and 12 weeks. Western blot analysis and real-time PCR showed that shock wave therapy significantly increased VEGF protein and mRNA expression, respectively, in the subchondral bone of the treated necrotic femoral heads. Compared with the contralateral control without shock wave treatment, the VEGF mRNA expression levels increased to a peak at 2 weeks after the shock wave treatment and remained high for 8 weeks, then declined at 12 weeks, whereas the VEGF protein expression levels increased to a peak at 4 weeks after the shock wave treatment and remained high for 12 weeks. The immunostaining of VEGF was weak in the control group, and the immunoreactivity level in the shock-wave-treated group increased at 4 weeks and persisted for 12 weeks. The most intensive VEGF immunoreactivity was observed in the proliferative zone above the necrotic zone. At 4, 8, and 12 weeks after the shock wave treatment, MVD in subchondral bone from treated femoral heads was significantly higher than that in subchondral bone from untreated femoral heads. These data clearly show that extracorporeal shock waves can significantly upregulate the expression of VEGF. The upregulation of VEGF may play a role in inducing the ingrowth of neovascularization and in improving the blood supply to the femoral head.

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References

  1. Graff J, Pastor J, Stnege T (1987) The effect of high energy shock waves on bony tissue: An experimental study. J Urol 137:278–281

    Google Scholar 

  2. Vogel J, Hopf C, Eysel P, Rompe JD (1997) Application of extracorporeal shock-waves in the treatment of pseudarthrosis of the lower extremity: Preliminary results. Arch Orthop Trauma Surg 116:480–483

    PubMed  CAS  Google Scholar 

  3. Valchanou VD, Michailov P (1991) High energy shock waves in the treatment of delayed and nonunion of fractures. Int Orthop 15:181–184

    Article  PubMed  CAS  Google Scholar 

  4. Haupt G (1997) Use of extracorporeal shock waves in the treatment of pseudoarthrosis, tendinopathy and other orthopedic diseases. J Urol 158:4–11

    Article  PubMed  CAS  Google Scholar 

  5. Crowther MA, Bannister GC, Huma H, Rooker GD (2002) A prospective, randomised study to compare extracorporeal shock-wave therapy and injection of steroid for the treatment of tennis elbow. J Bone Joint Surg Br 84:678–679

    Article  PubMed  CAS  Google Scholar 

  6. Haake M, Buch M, Schoellner C, Goebel F, Vogel M, Mueller I, Hausdorf J, Zamzow K, Schade-Brittinger C, Mueller HH (2003) Extracorporeal shock wave therapy for plantar fasciitis: Randomised controlled multicentre trial. Br Med J 327:75

    Article  Google Scholar 

  7. Loew M, Jurgowski W, Mau HC, Thomsen M (1995) Treatment of calcifying tendinitis of rotator cuff by extracorporeal shock waves: A preliminary report. J Shoulder Elbow Surg 4:101–106

    Article  PubMed  CAS  Google Scholar 

  8. Costa ML, Shepstone L, Donell ST, Thomas TL (2005) Shock wave therapy for chronic Achilles tendon pain: A randomized placebo-controlled trial. Clin Orthop 440:199–204

    Article  PubMed  CAS  Google Scholar 

  9. Wang CJ, Wang FS, Huang CC, Yang KD, Weng LH, Huang HY (2005) Treatment for osteonecrosis of the femoral head: Comparison of extracorporeal shock waves with core decompression and bone-grafting. J Bone Joint Surg Am 87:2380–2387

    Article  PubMed  Google Scholar 

  10. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  PubMed  CAS  Google Scholar 

  11. Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108:2369–2379

    PubMed  CAS  Google Scholar 

  12. Winet H (1996) The role of microvasculature in normal and perturbed bone healing as revealed by intravital microscopy. Bone 19(Suppl 1):39S–57S

    Article  PubMed  CAS  Google Scholar 

  13. Maier M, Milz S, Tischer T, Munzing W, Manthey N, Stabler A, Holzknecht N, Weiler C, Nerlich A, Refior HJ, Schmitz C (2002) Influence of extracorporeal shock-wave application on normal bone in an animal model in vivo. J Bone Joint Surg Br 84:592–599

    Article  PubMed  CAS  Google Scholar 

  14. Yamamoto T, Hirano K, Tsutsui H, Sugioka Y, Sueishi K (1995) Corticosteroid enhances the experimental induction of osteonecrosis in rabbits with Shwartzman reaction. Clin Orthop 316:235–243

    PubMed  Google Scholar 

  15. Chen YJ, Kuo YR, Yang KD, Wang CJ, Huang HC, Wang FS (2003) Shock wave application enhances pertussis toxin protein-sensitive bone formation of segmental femoral defect in rats. J Bone Miner Res 18:2169–2179

    Article  PubMed  Google Scholar 

  16. Wang CJ, Yang KD, Wang FS, Hsu CC, Chen HH (2004) Shock wave treatment shows dose-dependent enhancement of bone mass and bone strength after fracture of the femur. Bone 34:225–230

    Article  PubMed  Google Scholar 

  17. Musso ES, Mitchell SN, Schink-Ascani M, Bassett CAL (1986) Results of conservative management of osteonecrosis of the femoral head. Clin Orthop 207:209–215

    PubMed  Google Scholar 

  18. Takatori Y, Kokubo T, Ninomiya S, Nakamura S, Morimoto S, Kusaba I (1993) Avascular necrosis of the femoral head: Natural history and magnetic resonance imaging. J Bone Joint Surg Br 75:217–221

    PubMed  CAS  Google Scholar 

  19. Koo KH, Kim R, Ko GH, Song HR, Jeong ST, Cho SH (1995) Preventing collapse in early osteonecrosis of the femoral head: A randomised clinical trial of core decompression. J Bone Joint Surg Br 77:870–874

    PubMed  CAS  Google Scholar 

  20. Learmonth ID, Maloon S, Dall G (1990) Core decompression for early atraumatic osteonecrosis of the femoral head. J Bone Joint Surg Br 72:387–390

    PubMed  CAS  Google Scholar 

  21. Saito S, Ohzono K, Ono K (1988) Joint-preserving operations for idiopathic avascular necrosis of the femoral head: Results of core decompression, grafting and osteotomy. J Bone Joint Surg Br 70:78–84

    PubMed  CAS  Google Scholar 

  22. Wei SY, Klimkiewicz JJ, Lai M, Garino JP, Steinberg ME (1999) Revision total hip arthroplasty in patients with avascular necrosis. Orthopedics 22:747–757

    PubMed  CAS  Google Scholar 

  23. Zhang CQ, Zeng BF, Xu ZY, Song WQ, Shao L, Jing DX, Sui SP (2005) Treatment of femoral head necrosis with free vascularized fibula grafting: A preliminary report. Microsurgery 25:305–309

    Article  PubMed  Google Scholar 

  24. Wang CJ, Wang FS, Huang CC, Yang KD, Weng LH, Huang HY (2005) Treatment for osteonecrosis of the femoral head: Comparison of extracorporeal shock waves with core decompression and bone-grafting. J Bone Joint Surg Am 87:2380–2387

    Article  PubMed  Google Scholar 

  25. Lin PC, Wang CJ, Yang KD, Wang FS, Ko JY, Huang CC (2006) Extracorporeal shockwave treatment of osteonecrosis of the femoral head in systemic lupus erythematosus. J Arthroplasty 21:911–915

    Article  PubMed  Google Scholar 

  26. Ludwig J, Lauber S, Lauber HJ, Dreisilker U, Raedel R, Hotzinger H (2001) High-energy shock wave treatment of femoral head necrosis in adults. Clin Orthop 387:119–126

    Article  PubMed  Google Scholar 

  27. Ogden JA, Toth-Kischkat A, Schultheiss R (2001) Principles of shock wave therapy. Clin Orthop 387:8–17

    Article  PubMed  Google Scholar 

  28. Schaden W, Fischer A, Sailler A (2001) Extracorporeal shock wave therapy of nonunion or delayed osseous union. Clin Orthop 387:90–94

    Article  PubMed  Google Scholar 

  29. Wang FS, Yang KD, Kuo YR, Wang CJ, Sheen-Chen SM, Huang HC, Chen YJ (2003) Temporal and spatial expression of bone morphogenetic proteins in extracorporeal shock wave-promoted healing of segmental defect. Bone 32:387–396

    Article  PubMed  CAS  Google Scholar 

  30. Takahashi K, Yamazaki M, Saisu T, Nakajima A, Shimizu S, Mitsuhashi S, Moriya H (2004) Gene expression for extracellular matrix proteins in shockwave-induced osteogenesis in rats. Calcif Tissue Int 74:187–193

    Article  PubMed  CAS  Google Scholar 

  31. Gerber HP, Ferrara N (2000) Angiogenesis and bone growth. Trends Cardiovasc Med 10:223–228

    Article  PubMed  CAS  Google Scholar 

  32. Baron J, Klein KO, Yanovski JA, Novosad JA, Bacher JD, Bolander ME, Cutler GB Jr (1994) Induction of growth plate cartilage ossification by basic fibroblast growth factor. Endocrinology 135:2790–2793

    Article  PubMed  CAS  Google Scholar 

  33. Horner A, Bord S, Kemp P, Grainger D, Compston JE (1996) Distribution of platelet-derived growth factor (PDGF) A chain mRNA, protein, and PDGF-alpha receptor in rapidly forming human bone. Bone 19:353–362

    Article  PubMed  CAS  Google Scholar 

  34. Fiorelli G, Orlando C, Benvenuti S, Franceschelli F, Bianchi S, Pioli P, Tanini A, Serio M, Bartucci F, Brandi ML (1994) Characterization for insulin regulation, and function of specific cell membrane receptors like growth factor I on bone endothelial cells. J Bone Miner Res 9:329–337

    Article  PubMed  CAS  Google Scholar 

  35. Garcia-Ramirez M, Toran N, Andaluz P, Carrascosa A, Audi L (2000) Vascular endothelial growth factor is expressed in human fetal growth cartilage. J Bone Miner Res 15:534–540

    Article  PubMed  CAS  Google Scholar 

  36. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5:623–628

    Article  PubMed  CAS  Google Scholar 

  37. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  PubMed  CAS  Google Scholar 

  38. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442

    Article  PubMed  CAS  Google Scholar 

  39. Wang CJ, Wang FS, Yang KD, Weng LH, Hsu CC, Huang CS, Yang LC (2003) Shock wave therapy induces neovascularization at the tendon-bone junction. A study in rabbits. J Orthop Res 21:984–989

    Article  PubMed  Google Scholar 

  40. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5:623–628

    Article  PubMed  CAS  Google Scholar 

  41. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med 324:1–8

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (30571898).

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  1. Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, 200233, China

    Huan-Zhi Ma, Bing-Fang Zeng & Xiao-Lin Li

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  1. Huan-Zhi Ma
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  2. Bing-Fang Zeng
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Correspondence to Bing-Fang Zeng.

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Ma, HZ., Zeng, BF. & Li, XL. Upregulation of VEGF in Subchondral Bone of Necrotic Femoral Heads in Rabbits with Use of Extracorporeal Shock Waves. Calcif Tissue Int 81, 124–131 (2007). https://doi.org/10.1007/s00223-007-9046-9

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  • DOI: https://doi.org/10.1007/s00223-007-9046-9

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