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Gene intervention in ligament and tendon: current status, challenges, future directions

Gene Therapy volume 11, pages 368–378 (2004)Cite this article

Abstract

Ligament and tendon injuries are common clinical problems. Healing of these tissues occurs, but their properties do not return to normal. This predisposes to recurrent injuries, instability and arthritis, loss of motion and weakness. Gene therapy offers a novel approach to the repair of ligaments and tendons. Introduction of genes into ligaments and tendons using vectors has been successful. Marker genes and therapeutic genes have been introduced into both tissues with evidence of corresponding functional alterations. In addition, gene transfer has been used to manipulate the healing environment, opening the possibility of gene transfer to investigate ligament and tendon development and homeostasis, in addition to using this technology therapeutically. Several factors modulate the ‘success’ of gene transfer in these tissues.

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References

  1. Hildebrand KA, Frank CB . Ligaments: structure, function and response to injury and repair. In: Dee R, Hurst LC, Gruber MA, Kottmeier SA (eds) Principles of Orthopaedic Practice, 2nd ed. McGraw-Hill: New York, 1997, pp 109–117.

    Google Scholar 

  2. Woo SL-Y et al. Anatomy, biology, and biomechanics of tendon and ligament. In: Buckwalter JA, Einhorn TA, Simon SR (eds). Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, 2nd ed. 2000, pp 581–616.

  3. Hildebrand KA et al. The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament. Am J Sports Med 1998; 26: 549–554.

    Article  CAS  Google Scholar 

  4. Frank CB, Amiel D, Akeson WH . Healing of the medial collateral ligament of the knee. Acta Orthop Scand 1983; 54: 917–923.

    Article  CAS  Google Scholar 

  5. Thornton GM, Boorman RS, Shrive NG, Frank CB . Medial collateral ligament autografts have increased creep response for at least two years and early immobilization makes this worse. J Orthop Res 2002; 20: 346–352.

    Article  CAS  Google Scholar 

  6. Goldfarb CA et al. The effect of variations in applied rehabilitation force on collagen concentration and maturation at the intrasynovial flexor tendon repair site. J Hand Surgery 2001; 26A: 841–846.

    Article  Google Scholar 

  7. Seiler JGI et al. Autogenous flexor tendon grafts. Clin Orthop 1997; 345: 239–247.

    Article  Google Scholar 

  8. Gelbermann RH et al. The effect of gap formation at the repair site on the strength and excursion of intrasynovial flexor tendons: an experimental study on the early stages of tendon-healing in dogs. J Bone Joint Surg 1999; 81: 975–982.

    Article  Google Scholar 

  9. Manske PR . Flexor tendon healing. J Hand Surgery 1988; 13-B: 237–245.

    Article  Google Scholar 

  10. Lo IKY et al. The cellular networks of normal ovine medial collateral and anterior cruciate ligaments are not accurately recapitulated in scar tissue. J Anatomy 2002; 200: 283–296.

    Article  Google Scholar 

  11. Bray RC, Rangayyan RM, Frank CB . Normal and healing ligament vascularity: a quantitative histological assessment in the adult rabbit medial collateral ligament. J Anatomy 1996; 188: 87–95.

    Google Scholar 

  12. Ivie TJ, Bray RC, Salo PT . Denervation impairs healing of the rabbit medial collateral ligament. J Orthop Res 2002; 20: 990–995.

    Article  CAS  Google Scholar 

  13. Gronblad M et al. Immuno reactive neuropeptides in nerves in ligamentous tissue. An experimental neuroimmunohistochemical study. Clin Orthop 1991; 265: 291–296.

    Google Scholar 

  14. Ackerman PW et al. Anatomic innervation of tendons, ligaments and joint capsules. A morphologic and quantitative study in rats. J Orthop Res 2001; 19: 372–378.

    Article  Google Scholar 

  15. Amiel D et al. Tendons and ligaments: a morphological and biochemical comparison. J Orthop Res 1984; 1: 257–265.

    Article  CAS  Google Scholar 

  16. Nakamura N et al. Decorin antisense gene therapy improves functional healing of early rabbit ligament scar with enhanced collagen fibrillogenesis in vivo. J Orthop Res 2000; 18: 517–523.

    Article  CAS  Google Scholar 

  17. Hart DA et al. Complexity of determining cause and effect in vivo after antisense gene therapy. Clin Orthop 2000; 379S: S242–S251.

    Article  Google Scholar 

  18. Niyibizi C, Kavalkovich K, Woo SL-Y . Type V collagen is increased during rabbit medial collateral ligament healing. Knee Surgery Sports Traumatol 2000; 8: 281–285.

    Article  CAS  Google Scholar 

  19. Frank CB et al. Collagen fibril diameters in the healing adult rabbit medial collateral ligament. Connective Tissue Res 1991; 27: 251–263.

    Article  Google Scholar 

  20. Thornton GM, Boorman RS, Shrive NG, Frank CB . Early immobilization further impairs the inferior long-term creep behavior. 1999; 42: 391–392; The American Society of Mechanical Engineers. Bioengineering Conference 1999. Goel VK, Spilker RL, Ateshian GA, Soslowsky LJ.

  21. Majima T et al. Compressive compared with tensile loading of medial collateral ligament scar in vitro uniquely influences mRNA levels for aggrecan, collagen type II, and collagenase. J Orthop Res 2000; 18: 524–531.

    Article  CAS  Google Scholar 

  22. Banes AJ et al. PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon fibroblasts in vitro. J Biomech 1995; 28: 1505–1513.

    Article  CAS  Google Scholar 

  23. Bray RC, Butterwick DJ, Doschak MR, Tyberg JV . Coloured microsphere assesment of blood flow to knee ligaments in adult rabbits: effects of injury. J Orthop Res 1996; 14: 618–625.

    Article  CAS  Google Scholar 

  24. Hildebrand KA et al. Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: the use of different viral vectors and the effects of injury. J Orthop Res 1999; 17: 37–42.

    Article  CAS  Google Scholar 

  25. Menetrey J et al. Direct-, fibroblast- and myoblast-mediated gene transfer to the anterior cruciate ligament. Tissue Eng 1999; 5: 435–442.

    Article  CAS  Google Scholar 

  26. Gerich TG et al. Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing. Gene Therapy 1996; 3: 1089–1093.

    CAS  Google Scholar 

  27. Day CS et al. Myoblast-mediated gene transfer to the joint. J Orthop Res 1997; 15: 894–903.

    Article  CAS  Google Scholar 

  28. Nakamura N et al. A comparison of in vivo gene delivery methods for antisense therapy in ligament healing. Gene Therapy 1998; 5: 1455–1461.

    Article  CAS  Google Scholar 

  29. Sawchuk SJ et al. Anti-T cell receptor monoclonal antibody prolongs transgene expression following adenovirus-mediated in vivo gene transfer to mouse synovium. Human Gene Ther 996; 7: 499–506.

    Article  Google Scholar 

  30. Tripathy SK, Black HB, Goldwasser E, Leiden JM . Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 1996; 2: 545–550.

    Article  CAS  Google Scholar 

  31. Palmer TD, Rosman GJ, Osborne WRA, Miller AD . Genetically modified skin fibroblasts persist long after transplantation but gradually inactive introduced genes. Cell Biol 1991; 88: 1330–1334.

    CAS  Google Scholar 

  32. Nakamura N et al. Early biological effect of in vivo gene transfer of platelet-derived growth factor (PDGF)-B into healing patellar ligament. Gene Therapy 1998; 5: 1165–1170.

    Article  CAS  Google Scholar 

  33. Chimich D et al. The effects of initial end contact on medial collateral ligament healing: a morphological and biomechanical study in a rabbit model. J Orthop Res 1991; 9: 37–47.

    Article  CAS  Google Scholar 

  34. Santra M, Reed CC, Iozzo RV . Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. J Biol Chem 2002; 277: 35671–35681.

    Article  CAS  Google Scholar 

  35. Iozzo RV, Moscatello DK, McQuillan DJ, Eichstetter I . Decorin is a biological ligand for the epidermal growth factor receptor. J Biol Chem 1999; 274: 4489–4492.

    Article  CAS  Google Scholar 

  36. Patel S et al. Decorin activates the epidermal growth factor receptor and elevates cytosolic Ca2+ in A431 carcinoma cells. J Biol Chem 1998; 273: 3121–3124.

    Article  CAS  Google Scholar 

  37. Nakamura N et al. Transient introduction of a foreign gene into healing rat patellar ligament. J Clin Invest 1996; 97: 226–231.

    Article  CAS  Google Scholar 

  38. Lou J et al. BMP-12 gene transfer augmentation of lacerated tendon repair. J Orthop Res 2001; 19: 1199–1202.

    Article  CAS  Google Scholar 

  39. Lou J, Manske PR, Aoki M, Joyce ME . Adenovirus-mediated gene transfer into tendon and tendon sheath. J Orthop Res 1996; 14: 513–517.

    Article  CAS  Google Scholar 

  40. Lou J et al. In vivo gene transfer and overexpression of focal adhesion kinase (pp125FAK) mediated by recombinant adenovirus-induced tendon adhesion formation and epitendon cell change. J Orthop Res 1997; 15: 911–918.

    Article  CAS  Google Scholar 

  41. Goomer RS et al. Nonviral in vivo gene therapy for tissue engineering of articular cartilage and tendon repair. Clin Orthop 2000; 379S: S189–S200.

    Article  Google Scholar 

  42. Dai Q, Manfield L, Wang Y, Murrell GAC . Adenovirus-mediated gene transfer to healing tendon – enhanced efficiency using a gelatin sponge. J Orthop Res 2003; 21: 604–609.

    Article  CAS  Google Scholar 

  43. Özkan I et al. Direct in vivo gene transfer to healing rat patellar ligament by intra-arterial delivery of haemagglutinating virus of Japan liposomes. Eur J Clin Invest 1999; 29: 63–67.

    Article  Google Scholar 

  44. Hart DA, Evans CH . Breakout session 8: ligament and tendon. Clin Orthop 2000; 379S: S260–S261.

    Article  Google Scholar 

  45. Iozzo RV . The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol 1997; 32: 141–174.

    Article  CAS  Google Scholar 

  46. Bullard KM, Longaker MT, Lorenz HP . Fetal wound healing: current biology. World J Surg 2003; 27: 54–61.

    Article  Google Scholar 

  47. Peled ZM et al. Matrix metalloproteinases and the ontogeny of scarless repair: the other side of the wound healing balance. Plastic Reconstr Surg 2002; 110: 801–811.

    Article  Google Scholar 

  48. Malaviya P et al. An in vivo model for load-modulated remodeling in the rabbit flexor tendon. J Orthop Res 2000; 18: 116–125.

    Article  CAS  Google Scholar 

  49. Frank CB, Loitz BJ, Shrive NG . Injury location affects ligament healing. Acta Orthop Scand 1995; 66: 455–462.

    Article  CAS  Google Scholar 

  50. Hart DA et al. Similarities and differences between in vivo and in vitro analysis at the functional and molecular levels. Recent Res Dev Biophys Biochem 2002; 2: 153–177.

    CAS  Google Scholar 

  51. Lo IKY et al. The healing response of ACL and MCL injuries is initially similar but diverges with time. Proceedings of World Congress of Biomechanics 2002, Calgary, Canada: August.

  52. Thomas DR . Age related changes in wound healing. Drugs Aging 2001; 18: 607–620.

    Article  CAS  Google Scholar 

  53. Ashcroft GS, Mills SJ, Ashworth JJ . Ageing and wound healing. Biogerontology 2002; 3: 337–345.

    Article  CAS  Google Scholar 

  54. Ashcroft GS, Horan MA, Ferguson MWJ . Aging alter the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous healing. Lab Invest 1998; 78: 47–58.

    CAS  PubMed  Google Scholar 

  55. Hackman DJ, Ford HR . Cellular, biochemical and clinical aspects of wound healing. Surg Infect 2002; 3 (Suppl 1): 23–35.

    Google Scholar 

  56. Ashcroft GS et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta 1 levels. Nat Med 1997; 3: 1209–1215.

    Article  CAS  Google Scholar 

  57. Gallant CL, Wright JB, Olson ME, Hart DA . The red Duroc pig model of hypertrophic wound healing. Wound Repair Regeneration 2001; 9: 140.

    Google Scholar 

  58. Gallant CL, Olson ME, Hart DA . Skin wound healing in red Duroc pigs: potential role of growth factors and cytokines in scar formation. Wound Repair Regeneration 2002; 10: A19.

    Google Scholar 

  59. Gallant CL, Olson ME, Hart DA . Full- and partial-thickness skin wounds in red Duroc pigs leads to hypercontracted, hyperpigmented scars. Wound Repair Regeneration 2002; 10: A19.

    Google Scholar 

  60. Gallant CL, Olson ME, Hart DA . Molecular and histologic analysis of skin wound healing in Yorkshire X red Duroc F1 pigs: Evidence for the dominant influence of the red Duroc genetic contribution. Wound Repair Regeneration 2003; 11: A7.

    Google Scholar 

  61. Wang JF . Molecular and cell biology of skin wound healing in a pig model. Connective Tissue Res 2000; 41: 195–211.

    Article  CAS  Google Scholar 

  62. Wang JF . The pig as a model for excisional skin wound healing: characterization of the molecular and cellular biology, and bacteriology of the healing process. Compar Med 2001; 51: 341–348.

    CAS  Google Scholar 

  63. Bennett SP et al. Growth factors in the treatment of diabetic foot ulcers. Br J Surg 2003; 90: 133–146.

    Article  CAS  Google Scholar 

  64. Eming SA, Smola H, Krieg T . Treatment of chronic wounds: state of the art and future concepts. Cells Tissues Organs 2002; 172: 105–117.

    Article  CAS  Google Scholar 

  65. Pierce GF et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB. Am J Pathol 1994; 145: 1399–1410.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Evans CH, Robbins PD . Current concepts review: possible orthopaedic applications of gene therapy. J Bone Joint Surg 1995; 77: 1103–1114.

    Article  CAS  Google Scholar 

  67. Fisher AA et al. Evaluating the specificity of antisense oligonucleotide conjugates: a DNA array analysis. J Biol Chem 2002; 277: 22980–22984.

    Article  CAS  Google Scholar 

  68. Akeson W, Amiel D, Woo SL-Y . Immobility effects on synovial joints the pathomechanics of joint contracture. Biorheology 1980; 17: 95–110.

    Article  CAS  Google Scholar 

  69. Hildebrand KA et al. Myofibroblast numbers are elevated in human elbow joint capsules following trauma. Clin Orthop Relat Res 2004, In press.

  70. Hildebrand KA, Holmberg M, Shrive NG . A new method to measure post-traumatic joint contractures in the rabbit knee. J Biomech Eng 2004, In press.

  71. Hildebrand KA, Sutherland C . Post-traumatic rabbit knee joint contractures are permanent. Trans Orthop Res Soc 2003; 28: 1275.

    Google Scholar 

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Acknowledgements

We thank Carla Gronau for preparing the manuscript. Dr KA Hildebrand is a Clinical Investigator with the Alberta Heritage Foundation for Medical Research, Dr CB Frank is the McCaig Professor of Surgery, University of Calgary, and Dr DA Hart is the Calgary Foundation – Grace Glaum Professor in Arthritis Research, University of Calgary.

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  1. McCaig Centre for Joint Injury and Arthritis Research, University of Calgary, Calgary, AB, Canada

    KA Hildebrand, CB Frank & DA Hart

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Hildebrand, K., Frank, C. & Hart, D. Gene intervention in ligament and tendon: current status, challenges, future directions. Gene Ther 11, 368–378 (2004). https://doi.org/10.1038/sj.gt.3302198

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