Skip to main content
PMC home page
International Orthopaedics logoLink to International Orthopaedics
. 2005 May 18;29(4):205–209. doi: 10.1007/s00264-005-0650-x

Orthopaedic applications of gene therapy

Martin Lind 1,2,✉, Cody Bünger 1
PMCID: PMC3474530  PMID: 15900437

Abstract

Gene therapy presents a novel approach to biological treatment. Several orthopaedic diseases can cause changes in biological signalling at the tissue level that potentially can be repaired or modified by inserting genes into the cells or tissues to modulate gene expression. Impaired bone healing, need for extensive bone formation, cartilage repair and metabolic bone diseases are all conditions where alterations of the signalling peptides involved may provide cure or improvement. In orthopaedic oncology, gene therapy may achieve induction of tumour necrosis and increased tumour sensitivity to chemotherapy. In the last decade, extensive improvements have been made to optimise gene therapy and have been tested on several orthopaedic conditions. How far this development has come in orthopaedics is highlighted in this paper.

Full Text

The Full Text of this article is available as a PDF (88.2 KB).

Abbreviations

MSC

Mesenchymal stem cell

IGF

Insulin-like growth factor

BMP

Bone morphogenetic protein

TGF-beta

Transforming growth factor beta

OPG

Osteoprotegerin

RANKL

Receptor antagonist of the NF kappa beta ligand

CSF-1

Colony stimulating factor-1

TIMP-1

Tissue inhibitor of metalloproteinase

DDD

Degenerative disc disease

PDGF

Platelet-derived growth factor

LMP-1

LIM mineralization protein 1

TRAIL

TNF-related apoptosis-inducing ligand

References

  • 1.Abboud SL, Woodruff K, Liu C, Shen V, Ghosh-Choudhury N. Rescue of the osteopetrotic defect in op/op mice by osteoblast-specific targeting of soluble colony-stimulating factor-1. Endocrinology. 2002;143:1942–1949. doi: 10.1210/en.143.5.1942. [DOI] [PubMed] [Google Scholar]
  • 2.Baltzer AW, Lattermann C, Whalen JD, Wooley P, Weiss K, Grimm M, Ghivizzani SC, Robbins PD, Evans CH. Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther. 2000;7:734–739. doi: 10.1038/sj/gt/3301166. [DOI] [PubMed] [Google Scholar]
  • 3.Boden SD, Titus L, Hair G, Liu Y, Viggeswarapu M, Nanes MS, Baranowski C. Lumbar spine fusion by local gene therapy with a cDNA encoding a novel osteoinductive protein (LMP-1) Spine. 1998;23:2486–2492. doi: 10.1097/00007632-199812010-00003. [DOI] [PubMed] [Google Scholar]
  • 4.Bonadio J, Smiley E, Patil P, Goldstein S. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med. 1999;5:753–759. doi: 10.1038/10473. [DOI] [PubMed] [Google Scholar]
  • 5.Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine. 2002;27:2396–2408. doi: 10.1097/00007632-200211010-00015. [DOI] [PubMed] [Google Scholar]
  • 6.Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83(Suppl 1):S151–S158. [PMC free article] [PubMed] [Google Scholar]
  • 7.Goater JJ, O’Keefe RJ, Rosier RN, Puzas JE, Schwarz EM. Efficacy of ex vivo OPG gene therapy in preventing wear debris induced osteolysis. J Orthoptera Res. 2002;20:169–173. doi: 10.1016/S0736-0266(01)00083-3. [DOI] [PubMed] [Google Scholar]
  • 8.Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, Velde, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84:2123–2134. doi: 10.1302/0301-620X.84B5.12795. [DOI] [PubMed] [Google Scholar]
  • 9.Grande DA, Mason J, Light E, Dines D. Stem cells as platforms for delivery of genes to enhance cartilage repair. J Bone Joint Surg Am. 2003;85(Suppl 2):111–116. doi: 10.2106/00004623-200300002-00015. [DOI] [PubMed] [Google Scholar]
  • 10.Helm GA, Alden TD, Beres EJ, Hudson SB, Das S, Engh JA, Pittman DD, Kerns KM, Kallmes DF. Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. J Neurosurg Spine. 2000;92:191–196. doi: 10.1007/s005860000139. [DOI] [PubMed] [Google Scholar]
  • 11.Lehrman S. Virus treatment questioned after gene therapy death. Nature. 1999;401:517–518. doi: 10.1038/43977. [DOI] [PubMed] [Google Scholar]
  • 12.Lieberman JR, Daluiski A, Stevenson S, Wu L, McAllister P, Lee YP, Kabo JM, Finerman GA, Berk AJ, Witte ON. The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats. J Bone Joint Surg Am. 1999;81:905–917. doi: 10.2106/00004623-199907000-00002. [DOI] [PubMed] [Google Scholar]
  • 13.Lollo CP, Banaszczyk MG, Chiou HC. Obstacles and advances in non-viral gene delivery. Curr Opin Mol Ther. 2000;2:136–142. [PubMed] [Google Scholar]
  • 14.Moon SH, Gilbertson LG, Nishida K, Knaub M, Muzzonigro T, Robbins PD, Evans CH, Kang JD. Human intervertebral disc cells are genetically modifiable by adenovirus-mediated gene transfer: implications for the clinical management of intervertebral disc disorders. Spine. 2000;25:2573–2579. doi: 10.1097/00007632-200010150-00006. [DOI] [PubMed] [Google Scholar]
  • 15.Musgrave DS, Bosch P, Ghivizzani S, Robbins PD, Evans CH, Huard J. Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone. 1999;24:541–547. doi: 10.1016/S8756-3282(99)00086-1. [DOI] [PubMed] [Google Scholar]
  • 16.Nishida K, Kang JD, Gilbertson LG, Moon SH, Suh JK, Vogt MT, Robbins PD, Evans CH. Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine. 1999;24:2419–2425. doi: 10.1097/00007632-199912010-00002. [DOI] [PubMed] [Google Scholar]
  • 17.Nishida K, Kang JD, Suh JK, Robbins PD, Evans CH, Gilbertson LG. Adenovirus-mediated gene transfer to nucleus pulposus cells. Implications for the treatment of intervertebral disc degeneration. Spine. 1998;23:2437–2442. doi: 10.1097/00007632-199811150-00016. [DOI] [PubMed] [Google Scholar]
  • 18.Niyibizi C, Smith P, Mi Z, Phillips CL, Robbins P. Transfer of proalpha2(I) cDNA into cells of a murine model of human Osteogenesis Imperfecta restores synthesis of type I collagen comprised of alpha1(I) and alpha2(I) heterotrimers in vitro and in vivo. J Cell Biochem. 2001;83:84–91. doi: 10.1002/jcb.1209. [DOI] [PubMed] [Google Scholar]
  • 19.Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, Huard J. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest. 2002;110:751–759. doi: 10.1172/JCI200215153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ramnaraine M, Pan W, Goblirsch M, Lynch C, Lewis V, Orchard P, Mantyh P, Clohisy DR. Direct and bystander killing of sarcomas by novel cytosine deaminase fusion gene. Cancer Res. 2003;63:6847–6854. [PubMed] [Google Scholar]
  • 21.Riew KD, Wright NM, Cheng S, Avioli LV, Lou J. Induction of bone formation using a recombinant adenoviral vector carrying the human BMP-2 gene in a rabbit spinal fusion model. Calcif Tissue Int. 1998;63:357–360. doi: 10.1007/s002239900540. [DOI] [PubMed] [Google Scholar]
  • 22.Robbins PD, Ghivizzani SC. Viral vectors for gene therapy. Pharmacol Ther. 1998;80:35–47. doi: 10.1016/S0163-7258(98)00020-5. [DOI] [PubMed] [Google Scholar]
  • 23.Rutherford RB, Moalli M, Franceschi RT, Wang D, Gu K, Krebsbach PH. Bone morphogenetic protein-transduced human fibroblasts convert to osteoblasts and form bone in vivo. Tissue Eng. 2002;8:441–452. doi: 10.1089/107632702760184709. [DOI] [PubMed] [Google Scholar]
  • 24.Suzuki H, Hotta T, Koyama T, Komagata M, Imakiire A, Yanase N, Yoshimoto T, Mizuguchi J. Retrovirus-mediated transduction of TRAIL and chemotherapeutic agents co-operatively induce apoptotic cell death in both sarcoma and myeloma cells. Anticancer Res. 2003;23:3247–3253. [PubMed] [Google Scholar]
  • 25.Thompson JP, Oegema TR, Jr, Bradford DS. Stimulation of mature canine intervertebral disc by growth factors. Spine. 1991;16:253–260. doi: 10.1117/12.45701. [DOI] [PubMed] [Google Scholar]
  • 26.Turgeman G, Pittman DD, Muller R, Kurkalli BG, Zhou S, Pelled G, Peyser A, Zilberman Y, Moutsatsos IK, Gazit D. Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med. 2001;3:240–251. doi: 10.1002/1521-2254(200105/06)3:3<240::AID-JGM181>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  • 27.Wallach CJ, Sobajima S, Watanabe Y, Kim JS, Georgescu HI, Robbins P, Gilbertson LG, Kang JD. Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine. 2003;28:2331–2337. doi: 10.1097/01.BRS.0000085303.67942.94. [DOI] [PubMed] [Google Scholar]
  • 28.Zuk PA, Zhu M, Ashjian P, Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–4295. doi: 10.1091/mbc.E02-02-0105. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from International Orthopaedics are provided here courtesy of Springer-Verlag

RESOURCES