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Tendon and ligament engineering in the adult organism: mesenchymal stem cells and gene-therapeutic approaches

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Abstract

Tendons and ligaments are elastic collagenous tissues with similar composition and hierarchical structure, contributing to motion. Their strength is related to the number and size of the collagen fibrils. Collagen fibrils increase in size during development and in response to increased physical demands or training. Tendon disorders are commonly seen in clinical practice and give rise to significant morbidity. Treatment is difficult and patients often suffer from the symptoms for quite a long time. Despite remodelling, the biochemical and mechanical properties of healed tendon tissue never match those of intact tendon. The prerequisite for focussed treatment strategies in the future will be an improved understanding of the molecular events both in the embryo and contributing to regeneration in the adult organism. Novel approaches include the local delivery of growth factors, stem- and tendon-cell-derived therapy, the application of mechanical load and gene-therapeutic approaches based on vehicles encoding selected factors, or combinations of these. Important factors are proteins of the extracellular matrix like the metalloproteinases, growth factors like the bone morphogenetic proteins but also intracellular signalling mediator proteins, such as the Smads and transcription factors from the helix–loop–helix and other families. In this review, we focus specifically on such molecular approaches based on mesenchymal stem cells.

Résumé

Les tendons et les ligaments sont constitués de fibres élastiques de collagène dont la composition est similaire de même que leur structure contribuant au mouvement. Leur résistance est parallèle au nombre et à la taille des fibres collagènes. Si les fibres collagènes grossissent durant la croissance, il en est de même en réponse à une augmentation de l’entraînement physique. A titre clinique on rencontre relativement fréquemment les problèmes tendineux responsables d’une certaine morbidité. Le traitement en est difficile, les patients sont affectés sur un temps relativement long de troubles secondaires à ces lésions. En dépit du remodelage, les propriétés biomécaniques et biochimiques d’un tendon, d’un tissu tendineux guéri ne peuvent être comparés à ceux d’un tendon sain. Les prérequis d’une stratégie thérapeutique devrait, dans le futur, permettre de mieux comprendre ce qui se passe au moment du développement embryologique et de la régénération au niveau de l’organisme adulte. Une nouvelle approche thérapeutique doit prendre en compte l’administration de facteurs de croissance et l’utilisation de cellules souche dans le cadre d’une thérapie génique. Les facteurs importants sont les protéines de la matrice extracellulaire comme les métalloprotéinases de même que les facteurs de croissance de type BMP mais il faut prendre en compte également les facteurs de transcriptions chromosomiques. Pour cette étude, nous nous sommes spécialement centrés sur de telles molécules et sur les cellules souches mesenchymenteuses.

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References

  1. Aspenberg P, Forslund C (1999) Enhanced tendon healing with GDF 5 and 6. Acta Orthop Scand 70:51–54

    Article  PubMed  CAS  Google Scholar 

  2. Awad HA, Boivin GP, Dressler MR et al (2003) Repair of patellar tendon injuries using a cell-collagen composite. J Orthop Res 21:420–431

    Article  PubMed  CAS  Google Scholar 

  3. Awad HA, Butler DL, Boivin GP et al (1999) Autologous mesenchymal stem cell-mediated repair of tendon. Tissue Eng 5:267–277

    Article  PubMed  CAS  Google Scholar 

  4. Awad HA, Butler DL, Harris MT et al (2000) In vitro characterization of mesenchymal stem cell-seeded collagen scaffolds for tendon repair: effects of initial seeding density on contraction kinetics. J Biomed Mater Res 51:233–240

    Article  PubMed  CAS  Google Scholar 

  5. Batten ML, Hansen JC, Dahners LE (1996) Influence of dosage and timing of application of platelet-derived growth factor on early healing of the rat medial collateral ligament. J Orthop Res 14:736–741

    Article  PubMed  CAS  Google Scholar 

  6. Benjamin M, Ralphs JR (1996) Tendons in health and disease. Man Ther 1:186–191

    Article  PubMed  Google Scholar 

  7. Brent AE, Braun T, Tabin CJ (2005) Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development. Development 132:515–528

    Article  PubMed  CAS  Google Scholar 

  8. Brent AE, Schweitzer R, Tabin CJ (2003) A somitic compartment of tendon progenitors. Cell 113:235–248

    Article  PubMed  CAS  Google Scholar 

  9. Caplan AI (2005) Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics. Tissue Eng 11:1198–1211

    Article  PubMed  CAS  Google Scholar 

  10. Chhabra A, Tsou D, Clark RT et al (2003) GDF-5 deficiency in mice delays Achilles tendon healing. J Orthop Res 21:826–835

    Article  PubMed  CAS  Google Scholar 

  11. Cooper JA Jr, Bailey LO, Carter JN et al (2006) Evaluation of the anterior cruciate ligament, medial collateral ligament, achilles tendon and patellar tendon as cell sources for tissue-engineered ligament. Biomaterials 27:2747–2754

    Article  PubMed  CAS  Google Scholar 

  12. Forslund C, Aspenberg P (2003) Improved healing of transected rabbit Achilles tendon after a single injection of cartilage-derived morphogenetic protein-2. Am J Sports Med 31:555–559

    PubMed  Google Scholar 

  13. Forslund C, Rueger D, Aspenberg P (2003) A comparative dose–response study of cartilage-derived morphogenetic protein (CDMP)-1, -2 and -3 for tendon healing in rats. J Orthop Res 21:617–621

    Article  PubMed  CAS  Google Scholar 

  14. Garvin J, Qi J, Maloney M, Banes AJ (2003) Novel system for engineering bioartificial tendons and application of mechanical load. Tissue Eng 9:967–979

    Article  PubMed  CAS  Google Scholar 

  15. Gerich TG, Kang R, Fu FH et al (1997) Gene transfer to the patellar tendon. Knee Surg Sports Traumatol Arthrosc 5:118–123

    Article  PubMed  CAS  Google Scholar 

  16. Goh JC, Ouyang HW, Teoh SH et al (2003) Tissue-engineering approach to the repair and regeneration of tendons and ligaments. Tissue Eng 9(Suppl 1):S31–S44

    Article  PubMed  CAS  Google Scholar 

  17. Hildebrand KA, Deie M, Allen CR et al (1999) 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 17:37–42

    Article  PubMed  CAS  Google Scholar 

  18. Hildebrand KA, Woo SL, Smith DW et al (1998) The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament. An in vivo study. Am J Sports Med 26:549–554

    PubMed  CAS  Google Scholar 

  19. Hoffmann A, Gross G (2006) Tendon and ligament engineering: from cell biology to in vivo application. Regen Med 1:563–574

    Article  PubMed  CAS  Google Scholar 

  20. Hoffmann A, Pelled G, Turgeman G et al (2006) Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells. J Clin Invest 116:940–952

    Article  PubMed  CAS  Google Scholar 

  21. Holmbeck K, Bianco P, Caterina J et al (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99:81–92

    Article  PubMed  CAS  Google Scholar 

  22. Jozsa LG, Kannus P (1997) Human tendons: anatomy, physiology, and pathology. Human Kinetics, Champaign, Illinois

    Google Scholar 

  23. Juncosa-Melvin N, Boivin GP, Galloway MT et al (2005) Effects of cell-to-collagen ratio in mesenchymal stem cell-seeded implants on tendon repair biomechanics and histology. Tissue Eng 11:448–457

    Article  PubMed  CAS  Google Scholar 

  24. Kjaer M (2004) Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol Rev 84:649–698

    Article  PubMed  CAS  Google Scholar 

  25. Kjaer M, Langberg H, Miller BF et al (2005) Metabolic activity and collagen turnover in human tendon in response to physical activity. J Musculoskelet Neuronal Interact 5:41–52

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Lou J, Tu Y, Burns M et al (2001) BMP-12 gene transfer augmentation of lacerated tendon repair. J Orthop Res 19:1199–1202

    Article  PubMed  CAS  Google Scholar 

  28. Martin RB, Burr DB, Sharkey NA (1998) Skeletal tissue mechanics. Springer, New York

    Google Scholar 

  29. Mikic B, Schalet BJ, Clark RT et al (2001) GDF-5 deficiency in mice alters the ultrastructure, mechanical properties and composition of the Achilles tendon. J Orthop Res 19:365–371

    Article  PubMed  CAS  Google Scholar 

  30. Minamitani T, Ikuta T, Saito Y et al (2004) Modulation of collagen fibrillogenesis by tenascin-X and type VI collagen. Exp Cell Res 298:305–315

    Article  PubMed  CAS  Google Scholar 

  31. Nakamura N, Hart DA, Boorman RS et al (2000) Decorin antisense gene therapy improves functional healing of early rabbit ligament scar with enhanced collagen fibrillogenesis in vivo. J Orthop Res 18:517–523

    Article  PubMed  CAS  Google Scholar 

  32. Norris RA, Damon B, Mironov V et al (2007) Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J Cell Biochem 101:695–711

    Article  PubMed  CAS  Google Scholar 

  33. Oliver G, Wehr R, Jenkins NA et al (1995) Homeobox genes and connective tissue patterning. Development 121:693–705

    PubMed  CAS  Google Scholar 

  34. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233

    Article  PubMed  CAS  Google Scholar 

  35. Rees JD, Wilson AM, Wolman RL (2006) Current concepts in the management of tendon disorders. Rheumatology (Oxford) 45:508–521

    Article  CAS  Google Scholar 

  36. Schmidt CC, Georgescu HI, Kwoh CK et al (1995) Effect of growth factors on the proliferation of fibroblasts from the medial collateral and anterior cruciate ligaments. J Orthop Res 13:184–190

    Article  PubMed  CAS  Google Scholar 

  37. Schweitzer R, Chyung JH, Murtaugh LC et al (2001) Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128:3855–3866

    PubMed  CAS  Google Scholar 

  38. Settle SH Jr, Rountree RB, Sinha A et al (2003) Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev Biol 254:116–130

    Article  PubMed  CAS  Google Scholar 

  39. Sharma P, Maffulli N (2005) Basic biology of tendon injury and healing. Surgeon 3:309–316

    Article  PubMed  CAS  Google Scholar 

  40. Sharma P, Maffulli N (2006) Biology of tendon injury: healing, modeling and remodeling. J Musculoskelet Neuronal Interact 6:181–190

    PubMed  CAS  Google Scholar 

  41. Storm EE, Huynh TV, Copeland NG et al (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGFb-superfamily. Nature 368:639–643

    Article  PubMed  CAS  Google Scholar 

  42. Virchenko O, Fahlgren A, Skoglund B, Aspenberg P (2005) CDMP-2 injection improves early tendon healing in a rabbit model for surgical repair. Scand J Med Sci Sports 15:260–264

    Article  PubMed  CAS  Google Scholar 

  43. Wang Z, Juttermann R, Soloway PD (2000) TIMP-2 is required for efficient activation of proMMP-2 in vivo. J Biol Chem 275:26411–26415

    Article  PubMed  CAS  Google Scholar 

  44. Wolfman NM, Hattersley G, Cox K et al (1997) Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family. J Clin Invest 100:321–330

    Article  PubMed  CAS  Google Scholar 

  45. Xu PX, Cheng J, Epstein JA, Maas RL (1997) Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function. Proc Natl Acad Sci USA 94:11974–11979

    Article  PubMed  CAS  Google Scholar 

  46. Young RG, Butler DL, Weber W et al (1998) Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res 16:406–413

    Article  PubMed  CAS  Google Scholar 

  47. Zhang G, Ezura Y, Chervoneva I et al (2006) Decorin regulates assembly of collagen fibrils and acquisition of biomechanical properties during tendon development. J Cell Biochem 98:1436–1449

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the support from the EU integrated project GENOSTEM and by the SFB 599 collaborative research program of the German Research Foundation (DFG).

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Correspondence to Gerhard Gross.

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Hoffmann, A., Gross, G. Tendon and ligament engineering in the adult organism: mesenchymal stem cells and gene-therapeutic approaches. International Orthopaedics (SICO 31, 791–797 (2007). https://doi.org/10.1007/s00264-007-0395-9

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  • DOI: https://doi.org/10.1007/s00264-007-0395-9

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