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
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jones LC, Hungerford DS . The pathogenesis of osteonecrosis. Instr Course Lect 2007; 56: 179–196.
Mont MA, Jones LC, Hungerford DS . Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am 2006; 88: 1117–1132.
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.
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.
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.
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.
Lieberman JR . Core decompression for osteonecrosis of the hip. Clin Orthop Relat Res 2004; 418: 29–33.
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.
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.
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.
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.
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.
Maina F, Klein R . Hepatocyte growth factor, a versatile signal for developing neurons. Nat Neurosci 1999; 2: 213–217.
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.
Kosai K, Matsumoto K, Funakoshi H, Nakamura T . Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology 1999; 30: 151–159.
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.
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.
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.
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.
Deans RJ, Moseley AB . Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000; 28: 875–884.
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.
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.
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.
Saito S, Ohzono K, Ono K . Minimal osteonecrosis as a segmental infarct within the femoral head. Clin Orthop Relat Res 1988; 231: 35–50.
Arlet J . Nontraumatic avascular necrosis of the femoral head (past, present, and future). Clin Orthop 1992; 277: 12–21.
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.
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.
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.
Stella MC, Comoglio PM . HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol 1999; 31: 1357–1362.
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.
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.
Nakagami H, Kaneda Y, Ogihara T, Morishita R . Hepatocyte growth factor as potential cardiovascular therapy. Expert Rev Cardiovasc Ther 2005; 3: 513–519.
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.
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.
di Mari JF, Davis R, Safirstein RL . MAPK activation determines renal epithelial cell survival during oxiative injury. Am J Physiol 1999; 277: F195–F203.
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.
Deans RJ, Moseley AB . Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000; 28: 875–884.
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.
Hattori T . Experimental investigations of osteogenesis and chondrogenesis by implant of BMP-fibrin glue mixture. Nippon Seikeigeka Gakkai Zasshi 1990; 64: 824–834.
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.
Gibble JW, Ness PM . Fibrin glue: the perfect operative sealant? Transfusion 1990; 30: 741–747.
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.
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.
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
Corresponding authors
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gt.2008.110
Keywords
This article is cited by
-
Stem cell therapy for treating osteonecrosis of the femoral head: From clinical applications to related basic research
Stem Cell Research & Therapy (2018)
-
Metabolomic study of the bone trabecula of osteonecrosis femoral head patients based on UPLC–MS/MS
Metabolomics (2016)
-
Osteonecrosis of the femoral head: treatment with ancillary growth factors
Current Reviews in Musculoskeletal Medicine (2015)
-
Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review
BMC Musculoskeletal Disorders (2014)
-
Pro-osteogenic effects of fibrin glue in treatment of avascular necrosis of the femoral head in vivo by hepatocyte growth factor-transgenic mesenchymal stem cells
Journal of Translational Medicine (2014)