Skip to main content

Advertisement

SpringerLink
Log in

Development of a Cyclosporin-A-Induced Immune Tolerant Rat Model to Test Marrow Allograft Cell Type Effects on Bone Repair

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Bone repair is an important concept in tissue engineering, and the ability to repair bone in hypotrophic conditions such as that of irradiated bone, represents a challenge for this field. Previous studies have shown that a combination of bone marrow and (BCP) was effective to repair irradiated bone. However, the origin and role played by each cell type in bone healing still remains unclear. In order to track the grafted cells, the development of an animal model that is immunotolerant to an allograft of bone marrow would be useful. Furthermore, because the immune system interacts with bone turnover, it is of critical importance to demonstrate that immunosuppressive drugs do not interfere with bone repair. After a preliminary study of immunotolerance, cyclosporin-A was chosen to be used in immunosuppressive therapy. Ten rats were included to observe qualitative and quantitative bone repair 8 days and 6 weeks after the creation of bone defects. The defects were filled with an allograft of bone marrow alone or in association with BCP under immunosuppressive treatment (cyclosporin-A). The results showed that there was no significant interaction of cyclosporin-A with osseous regeneration. The use of this new immunotolerant rat model of bone marrow allograft in future studies will provide insight on how the cells within the bone marrow graft contribute to bone healing, especially in irradiated conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Mueller CK, Schultze-Mosgau S (2009) Radiation-induced microenvironments–the molecular basis for free flap complications in the pre-irradiated field? Radiother Oncol 93:581–585

    Article  CAS  PubMed  Google Scholar 

  2. Malard O, Guicheux J, Bouler J-M, Gauthier O, de Montreuil CB, Aguado E, Pilet P, LeGeros R, Daculsi G (2005) Calcium phosphate scaffold and bone marrow for bone reconstruction in irradiated area: a dog study. Bone 36:323–330

    Article  CAS  PubMed  Google Scholar 

  3. Lerouxel E, Weiss P, Giumelli B, Moreau A, Pilet P, Guicheux J, Corre P, Bouler JM, Daculsi G, Malard O (2006) Injectable calcium phosphate scaffold and bone marrow graft for bone reconstruction in irradiated areas: an experimental study in rats. Biomaterials 27:4566–4572

    Article  CAS  PubMed  Google Scholar 

  4. Espitalier F, Vinatier C, Lerouxel E, Guicheux J, Pilet P, Moreau F, Daculsi G, Weiss P, Malard O (2009) A comparison between bone reconstruction following the use of mesenchymal stem cells and total bone marrow in association with calcium phosphate scaffold in irradiated bone. Biomaterials 30:763–769

    Article  CAS  PubMed  Google Scholar 

  5. Khosla S, Westendorf JJ, Oursler MJ (2008) Building bone to reverse osteoporosis and repair fractures. J Clin Invest 118:421–428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Boukhechba F, Balaguer T, Bouvet-Gerbettaz S, Michiels JF, Bouler JM, Carle GF, Scimeca JC, Rochet N (2011) Fate of bone marrow stromal cells in a syngenic model of bone formation. Tissue Eng Part A 17:2267–2278

    Article  CAS  PubMed  Google Scholar 

  7. Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP (2007) Stem cell transplantation: the lung barrier. Transplant Proc 39:573–576

    Article  CAS  PubMed  Google Scholar 

  8. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ (2009) Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5:54–63

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Perrot P, Rousseau J, Bouffaut AL, Rédini F, Cassagnau E, Deschaseaux F, Heymann MF, Heymann D, Trichet V, Gouin F (2010) Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS One 5:e10999

    Article  PubMed Central  PubMed  Google Scholar 

  10. Hernigou P, Flouzat Lachaniette CH, Delambre J, Chevallier N, Rouard H (2014) Regenerative therapy with mesenchymal stem cells at the site of malignant primary bone tumour resection: what are the risks of early or late local recurrence? Int Orthop 38:1825–1835

    Article  PubMed  Google Scholar 

  11. Takayanagi H, Sato K, Takaoka A, Taniguchi T (2005) Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev 208:181–193

    Article  CAS  PubMed  Google Scholar 

  12. Hakamata Y, Tahara K, Uchida H, Sakuma Y, Nakamura M, Kume A et al (2001) Green fluorescent protein-transgenic rat: a tool for organ transplantation research. Biochem Biophys Res Commun 286:779–785

    Article  CAS  PubMed  Google Scholar 

  13. Rosenzweig M, Connole M, Glickman R, Yue SP, Noren B, DeMaria M, Johnson RP (2001) Induction of cytotoxic T lymphocyte and antibody responses to enhanced green fluorescent protein following transplantation of transduced CD34(+) hematopoietic cells. Blood 97:1951–1959

    Article  CAS  PubMed  Google Scholar 

  14. Skedros JG, Bloebaum RD, Bachus KN, Boyce TM, Constantz B (1993) Influence of mineral content and composition on graylevels in backscattered electron images of bone. J Biomed Mater Res 27:57–64

    Article  CAS  PubMed  Google Scholar 

  15. Grove JE, Bruscia E, Krause DS (2004) Plasticity of bone marrow-derived stem cells. Stem Cells 22:487–500

    Article  PubMed  Google Scholar 

  16. Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS (2004) Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305:90–93

    Article  CAS  PubMed  Google Scholar 

  17. Prockop DJ (2009) Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther 17:939–946

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Tsujigiwa H, Hirata Y, Katase N, Buery RR, Tamamura R, Ito S, Takagi S, Ida S, Nagatsuka H (2013) The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model. Calcif Tissue Int 92:296–306

    Article  CAS  PubMed  Google Scholar 

  19. Keown PA, Stiller CR (1987) Cyclosporine: a double-edged sword. Hosp Pract (Off Ed) 22(207–215):219–220

    Google Scholar 

  20. Orcel P, Denne MA, de Vernejoul MC (1991) Cyclosporin-A in vitro decreases bone resorption, osteoclast formation, and the fusion of cells of the monocyte-macrophage lineage. Endocrinology 128:1638–1646

    Article  CAS  PubMed  Google Scholar 

  21. Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S (1988) Cyclosporin-A in vivo produces severe osteopenia in the rat: effect of dose and duration of administration. Endocrinology 123:2571–2577

    Article  CAS  PubMed  Google Scholar 

  22. Matsunaga T, Shigetomi M, Hashimoto T, Suzuki H, Gondo T, Tanaka H, Sugiyama T, Taguchi T (2007) Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats. Osteoporos Int 18:1531–1540

    Article  CAS  PubMed  Google Scholar 

  23. Warren SB, Pelker RR, Friedlaender GE (1985) Effects of short-term cyclosporin-A on biomechanical properties of intact and fractured bone in the rat. J Orthop Res 3:96–100

    Article  CAS  PubMed  Google Scholar 

  24. Lerouxel E, Moreau A, Bouler JM, Giumelli B, Daculsi G, Weiss P, Malard O (2009) Effects of high doses of ionising radiation on bone in rats: a new model for evaluation of bone engineering. Br J Oral Maxillofac Surg 47:602–607

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants from ‘‘les gueules cassées’’ foundation and Sanofi Aventis Laboratories (perspectives ORL 2009). We thank Biomatlante (Vigneux de Bretagne, France) for supplying materials. We thank Dr Françoise Accard and Dr Antoine Rouger for their contribution to this work.

Conflict of Interest

The authors declare no conflict of interest.

Human and Animal Rights and Informed Consent

All the animals were provided by a certified breeding center (R. Janvier, Le Genest St. Isle, France). Animal care was provided by the Experimental Therapeutic Unit (Faculty of Medicine of Nantes, France), in accordance with the institutional guidelines of the French Ethical Committee (CEEA.PdL.06) for conducting animal experiments. The European Community Guidelines for the Care and Use of Laboratory Animals (DE 86/609/CEE, modified DE 2003/65/CE) have been revised by the European Directive 2010 (DE 2010/63/UE modified 22/09/2010). The adoption of the UE regulations into the French guidelines is effective as of January 1, 2013. Submission of the project to the new Ethical Committee of the “Pays de la Loire” was not mandatory until January 1, 2013. Nevertheless, all of the experiments conducted prior to January 2013 were performed according to these new regulations.

Author information

Author notes

    Authors and Affiliations

    1. INSERM, UMRS 791, Laboratoire d’ingénierie ostéo-articulaire et dentaire, LIOAD, 1 place Alexis Ricordeau, 44042, Nantes Cedex 1, France

      Florent Espitalier, Nicolas Durand, Pierre Corre, Sophie Sourice, Paul Pilet, Pierre Weiss, Jérôme Guicheux & Olivier Malard

    2. Service d’oto-rhino-laryngologie et de chirurgie cervico-faciale, Centre Hospitalier Universitaire de Nantes, 1 place Alexis Ricordeau, 44093, Nantes Cedex 1, France

      Florent Espitalier, Nicolas Durand & Olivier Malard

    3. Université de Nantes, UFR Odontologie, 1 place Alexis Ricordeau, 44042, Nantes Cedex 1, France

      Florent Espitalier, Pierre Weiss & Jérôme Guicheux

    4. Centre Hospitalier Universitaire de Nantes, Pôle hospitalo-universitaire 4 OTONN, Nantes Cedex 1, France

      Florent Espitalier, Nicolas Durand, Pierre Corre, Pierre Weiss, Jérôme Guicheux & Olivier Malard

    5. INSERM, U643, 30 Boulevard Jean Monnot, 44093, Nantes Cedex 1, France

      Séverine Rémy

    6. Service de stomatologie et de chirurgie maxillo-faciale, Centre Hospitalier Universitaire de Nantes, 1 place Alexis Ricordeau, 44093, Nantes Cedex 1, France

      Pierre Corre

    Authors
    1. Florent Espitalier
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Nicolas Durand
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Séverine Rémy
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Pierre Corre
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Sophie Sourice
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Paul Pilet
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Pierre Weiss
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jérôme Guicheux
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Olivier Malard
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Florent Espitalier.

    Additional information

    Florent Espitalier and Nicolas Durand have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Espitalier, F., Durand, N., Rémy, S. et al. Development of a Cyclosporin-A-Induced Immune Tolerant Rat Model to Test Marrow Allograft Cell Type Effects on Bone Repair. Calcif Tissue Int 96, 430–437 (2015). https://doi.org/10.1007/s00223-015-9970-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00223-015-9970-z

    Keywords

    Search

    Navigation