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Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model

Gene Therapy volume 15, pages 1139–1146 (2008)Cite this article

Abstract

The aim of our study was to evaluate the histological and biomechanical effects of BMP-12 gene transfer on the healing of rat Achilles tendons using a new approach employing a genetically modified muscle flap. Biopsies of autologous skeletal muscle were transduced with a type-five, first-generation adenovirus carrying the human BMP-12 cDNA (Ad.BMP-12) and surgically implanted around experimentally transected Achilles tendons in a rat model. The effect of gene transfer on healing was evaluated by mechanical and histological testing after 1, 2, 4 and 8 weeks. One week after surgery, the maximum failure load of the healing tendons was significantly increased in the BMP-12 group, compared with the controls, and the tendon stiffness was significantly higher at 1, 2 and 4 weeks. Moreover, the size of the rupture callus was increased in the presence of BMP-12 and there was evidence of accelerated remodeling of the lesion in response to BMP-12. Histological examination showed a much more organized and homogeneous pattern of collagen fibers at all time points in lesions treated with the BMP-12 cDNA muscle graft. Both single fibrils and the collagen fibers had a greater diameter, with a higher degree of collagen crimp than the collagen of the control groups. This was confirmed by sirius red staining in conjunction with polarized light microscopy, which showed a higher shift of small yellow-green fibers to strong yellow-orange fibers after 2, 4 and 8 weeks in the presence of BMP-12 cDNA. There was also an earlier shift from fibroblasts to fibrocytes within the healing tendon, with less fat cells present in the tendons of the BMP-12 group compared with the controls. Treatment with BMP-12 cDNA-transduced muscle grafts thus produced a promising acceleration and improvement of tendon healing, particularly influencing early tissue regeneration, leading to quicker recovery and improved biomechanical properties of the Achilles tendon. Further development of this approach could have clinical applications.

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Acknowledgements

This work was supported by Swiss National Science Foundation (310000-112033). We are grateful to Mrs H Schaller and Mrs C Pilapil for histology preparation, Dr H Clahsen and Mrs E Krott for assistance during histology examination, PD Dr L Dürselen for help during biomechanical testing, R Flückiger Ph.D. for critical reading the paper and Wyeth Pharmaceuticals (Cambridge MA) for kindly providing the adenovirus carrying the human BMP-12 cDNA.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery and Traumatology, Universitätsklinik Basel, Basel, Switzerland

    M Majewski

  2. Center for Molecular Orthopaedics, Harvard Medical School, Boston, MA, USA

    O Betz, F Liu, R M Porter & C H Evans

  3. Department of Orthopaedic Surgery, Sankt Anna Klinik, Luzern, Switzerland

    P E Ochsner

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  1. M Majewski
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  2. O Betz
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  3. P E Ochsner
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  4. F Liu
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  5. R M Porter
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  6. C H Evans
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Correspondence to M Majewski.

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Majewski, M., Betz, O., Ochsner, P. et al. Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther 15, 1139–1146 (2008). https://doi.org/10.1038/gt.2008.48

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