Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Treatment of avascular necrosis of the femoral head by hepatocyte growth factor-transgenic bone marrow stromal stem cells

Abstract

The treatment of hormone-induced early-stage avascular necrosis of the femoral head (ANFH) with transplantation of hepatocyte growth factor (HGF)-transgenic bone marrow stromal stem cells (BMSCs) was examined. A rabbit model of hormone-induced early ANFH was first established. BMSCs were transplanted by core decompression under the guidance of computed tomography (CT). A supportive fibrinogen drug delivery mixture (FG) was tested for mechanical enhancement of stem cell delivery. Therapeutic efficacy was evaluated by CT, magnetic resonance imaging (MRI), CT perfusion imaging, ink artery infusion angiography, hematoxylin-and-eosin staining and immunohistochemical staining for extracellular signal-regulated kinase-1/2 of pathological sections. A regular arrangement of trabeculae and obvious bone regeneration were observed in the animals receiving transplanted transgenic BMSCs with FG. Newly generated capillaries were visible on the bone plates of the trabeculae, and the bone marrow was rich in hematopoietic tissue. These results demonstrate that the combination of core decompression and transplantation of HGF transgenic autologous BMSCs enhanced blood vessel regeneration and bone reconstruction in the ANFH model. This study provides experimental data that motivate possible clinical use of this therapeutic strategy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Jones LC, Hungerford DS . The pathogenesis of osteonecrosis. Instr Course Lect 2007; 56: 179–196.

    PubMed  Google Scholar 

  2. Mont MA, Jones LC, Hungerford DS . Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am 2006; 88: 1117–1132.

    PubMed  Google Scholar 

  3. Ito H, Matsuno T, Omizu N, Aoki Y, Minami A . Mid-term prognosis of non-traumatic osteonecrosis of the femoral head. J Bone Joint Surg Br 2003; 85: 796–801.

    Article  CAS  Google Scholar 

  4. Steinberg ME, Larcom PG, Stafford BB, Hosick WB, Corces A, Bands RE et al. Treatment of osteonecrosis of the femoral head by core decompression, bone grafting, and electrical stimulation. In: Urbaniak JR, Jones JP (eds). Osteonecrosis: Etiology, Diagnosis, and Treatment. American Academy of Orthopaedic Surgeons: Rosemont, IL, 1997, pp 293–299.

    Google Scholar 

  5. Stulberg BN, Davis AW, Bauer TW, Levine M, Easley K . Osteonecrosis of the femoral head. A prospective randomized treatment protocol. Clin Orthop 1991; 268: 140–151.

    Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Lieberman JR . Core decompression for osteonecrosis of the hip. Clin Orthop Relat Res 2004; 418: 29–33.

    Article  Google Scholar 

  8. Nakamura T, Nawa K, Ichihara A . Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 1984; 122: 1450–1459.

    Article  CAS  Google Scholar 

  9. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440–443.

    Article  CAS  Google Scholar 

  10. Nakamura Y, Morishita R, Higaki J, Kida I, Aoki M, Moriguchi A et al. Hepatocyte growth factor (HGF) is a novel member of endothelium-specific growth factors: additive stimulatory effect of HGF with basic fibroblast growth factor, but not vascular endothelial growth factor. J Hypertens 1996; 14: 1067–1072.

    Article  CAS  Google Scholar 

  11. Nakamura Y, Morishita R, Nakamura S, Aoki M, Moriguchi A, Matsumoto K et al. A vascular modulator, hepatocyte growth factor, is associated with systolic pressure. Hypertension 1996; 28: 409–413.

    Article  CAS  Google Scholar 

  12. Liu Y, Sun AM, Dworkin LD . Hepatocyte growth factor protects renal epithelial cells from apoptotic cell death. Biochem Biophys Res Commun 1998; 246: 821–826.

    Article  CAS  Google Scholar 

  13. Maina F, Klein R . Hepatocyte growth factor, a versatile signal for developing neurons. Nat Neurosci 1999; 2: 213–217.

    Article  CAS  Google Scholar 

  14. Kosai K, Matsumoto K, Nagata S, Tsujimoto Y, Nakamura T . Abrogation of Fas-induced fulminant hepatic failure in mice by hepatocyte growth factor. Biochem Biophys Res Commun 1998; 244: 683–690.

    Article  CAS  Google Scholar 

  15. Kosai K, Matsumoto K, Funakoshi H, Nakamura T . Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology 1999; 30: 151–159.

    Article  CAS  Google Scholar 

  16. Yo Y, Morishita R, Yamamoto K, Tomita N, Kida I, Hayashi S et al. Actions of hepatocyte growth factor as a local modulator in the kidney: potential role in pathogenesis of renal disease. Kid Int 1998; 53: 50–58.

    Article  CAS  Google Scholar 

  17. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  18. Tsuchida H, Hashimoto J, Crawford E, Manske P, Lou J . Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats. J Orthop Res 2003; 21: 44–53.

    Article  Google Scholar 

  19. Pelissier P, Villars F, Mathoulin-Pelissier S, Bareille R, Lafage-Proust MH, Vilamitjana-Amedee J . Influences of vascularization and osteogenic cells on heterotopic bone formation within a madreporic ceramic in rats. Plast Reconstr Surg 2003; 111: 932–941.

    Google Scholar 

  20. Deans RJ, Moseley AB . Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000; 28: 875–884.

    Article  CAS  Google Scholar 

  21. Bruder SP, Jaiswal N, Ricalton NS, Mosca JD, Kraus KH, Kadiyala S . Mesenchymal stem cells in osteobiology and applied bone regeneration. Clin Orthop Relat Res 1998; 355: S247–S256.

    Article  Google Scholar 

  22. Lee K, Majumdar MK, Buyaner D, Hendricks JK, Pittenger MF, Mosca JD . Human mesenchymal stem cells maintain transgene expression during expansion and differentiation. Mol Ther 2001; 3: 857–866.

    Article  CAS  Google Scholar 

  23. Gangji V, Hauzeur JP, Matos C, De Maertelaer V, Toungouz M, Lambermont M . Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. A pilot study. J Bone Joint Surg Am 2004; 86-A: 1153–1160.

    Article  Google Scholar 

  24. Saito S, Ohzono K, Ono K . Minimal osteonecrosis as a segmental infarct within the femoral head. Clin Orthop Relat Res 1988; 231: 35–50.

    Google Scholar 

  25. Arlet J . Nontraumatic avascular necrosis of the femoral head (past, present, and future). Clin Orthop 1992; 277: 12–21.

    Google Scholar 

  26. Tio RA, Tkebuchava T, Scheuermann TH, Lebherz C, Magner M, Kearny M et al. Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium. Hum Gene Ther 1999; 10: 2953–2960.

    Article  CAS  Google Scholar 

  27. Hariawala MD, Horowitz JR, Esakof D, Sheriff DD, Walter DH, Keyt B et al. VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts. J Surg Res 1996; 63: 77–82.

    Article  CAS  Google Scholar 

  28. Garcia-Martinez C, Opolon P, Trochon V, Chianale C, Musset K, Lu H et al. Angiogenesis induced in muscle by a recombinant adenovirus expressing functional isoforms of basic fibroblast growth factor. Gen Ther 1999; 6: 1210–1221.

    Article  CAS  Google Scholar 

  29. Stella MC, Comoglio PM . HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol 1999; 31: 1357–1362.

    Article  CAS  Google Scholar 

  30. Taniyama Y, Morishita R, Aoki M, Hiraoka K, Yamasaki K, Hashiya N et al. Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy. Hypertension 2002; 40: 47–53.

    Article  CAS  Google Scholar 

  31. Stuart KA, Riordan SM, Lidder S, Crostella L, Williams R, Skouteris GG . Hepatocyte growth factor/scatter factor-induced intracellular signaling. Int J Exp Pathol 2000; 81: 17–30.

    Article  CAS  Google Scholar 

  32. Nakagami H, Kaneda Y, Ogihara T, Morishita R . Hepatocyte growth factor as potential cardiovascular therapy. Expert Rev Cardiovasc Ther 2005; 3: 513–519.

    Article  CAS  Google Scholar 

  33. Funatsu T, Sawa Y, Ohtake S, Takahashi T, Matsumiya G, Matsuura N et al. Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor. J Thorac Cardiovasc Surg 2002; 124: 1099–1105.

    Article  CAS  Google Scholar 

  34. Wu DL, Zhang YR, Lao MF, Yuan LZh, Wang L, Ha XQ et al. Gene therapy of canine myocardial ischemia with recombinant adenovirus carrying hepatocyte growth factor. Chin Sci Bull 2004; 49: 1278–1282.

    Article  Google Scholar 

  35. di Mari JF, Davis R, Safirstein RL . MAPK activation determines renal epithelial cell survival during oxiative injury. Am J Physiol 1999; 277: F195–F203.

    CAS  PubMed  Google Scholar 

  36. Yang C, Yang ShH, Du JY, Xiao BJ, Li J, Ye ShN . To enhance the repair of avascular necrosis of the femoral head with vascular endothelial growth factor gene transfection. J Clin Orthop 2004; 7: 90–93.

    Google Scholar 

  37. Deans RJ, Moseley AB . Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000; 28: 875–884.

    Article  CAS  Google Scholar 

  38. Wang WZh, Xing GY, Zhang KCh, Ma LG, Bai XD, Li B . Treatment of avascular necrosis of femoral head by core decompression and autograft of mesenchymal stem cells. J Chin Phys 2006; 8: 436–439.

    Google Scholar 

  39. Hattori T . Experimental investigations of osteogenesis and chondrogenesis by implant of BMP-fibrin glue mixture. Nippon Seikeigeka Gakkai Zasshi 1990; 64: 824–834.

    CAS  PubMed  Google Scholar 

  40. Kim NH, Yang KH, Lee HM, Oh SH . Effect of porcine bone morphogenetic protein on healing of bone defect in the rabbit radius. Yonsei Med J Mar 1992; 33: 54–63.

    Article  CAS  Google Scholar 

  41. Gibble JW, Ness PM . Fibrin glue: the perfect operative sealant? Transfusion 1990; 30: 741–747.

    Article  CAS  Google Scholar 

  42. Peng Songlin, Fang Huang, Chen Anming . Biocompatibility studies on fibrin glue cultured with bone marrow mesenchymal stem cells. Orthop Biomech Materials Clin Study 2004; 1: 34–37.

    Google Scholar 

  43. Ugai H, Yamasaki T, Hirose M, Inabe K, Kujime Y, Terashima M . Purification of infectious adenovirus in two hours by ultracentrifugation and tangential flow filtration. Biochem Biophys Res Commun 2005; 331: 1053–1060.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by State 863 Projects (2007AA02Z458), Science and Technology Project of Guangdong Province (2005B34001004), Science and Technology Project of Guangzhou (2005Z3-E0151) and the Medical Science Research Fund of Guangdong Province (B2005083, B2007107).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to L Ma or X-N Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wen, Q., Ma, L., Chen, YP. et al. Treatment of avascular necrosis of the femoral head by hepatocyte growth factor-transgenic bone marrow stromal stem cells. Gene Ther 15, 1523–1535 (2008). https://doi.org/10.1038/gt.2008.110

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.110

Keywords

This article is cited by

Search

Quick links