Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta

Nature Medicine volume 5, pages 309–313 (1999)Cite this article

Abstract

In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5–2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Flow cytometric analysis of cultured osteoblasts to exclude the presence of contaminating lymphohemopoietic cells.
Figure 2: a, Fluorescence in situ hybridization analysis of interphase nuclei from the cultured osteoblasts of patient 1 on day 101 after transplantation.
Figure 3: a, Biopsy specimen of trabecular bone before transplantation, stained with Goldners-Masson trichrome.
Figure 4: a, Growth rates of the patients during the 6 months immediately before (▪) and after (░) transplantation.

References

  1. Rickard, D.J., Sullivan, T.A., Shenker, B.J., Leboy, P.S. & Kazhdan, I. Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethasone and BMP-2. Dev. Biol. 161, 218–228 (1993).

    Article  Google Scholar 

  2. Malaval, L., Modrowski, D., Gupta, A.K. & Aubin, J.E. Cellular expression of bone-related proteins during in vitro osteogenesis in rat bone marrow stromal cell cultures. J. Cell. Physiol. 158, 555–572 (1994).

    Article  CAS  Google Scholar 

  3. Goshima, J., Goldberg, V. & Caplan, A. The osteogenic potential of culture expanded rat marrow mesenchymal cells assayed in vivo in calcium phosphate ceramic blocks. Clin. Orthop. 262, 298– 311 (1991).

    Google Scholar 

  4. Ohgushi, H., Goldberg, V.M. & Caplan, A.I. Repair of bone defects with marrow cells and porous ceramic: Experiments in rats. Acta Orthop. Scand. 60 , 334–339 (1989).

    Article  CAS  Google Scholar 

  5. Nakahara, H., Goldberg, V.M. & Caplan, A.I. Culture-expanded human periosteal-derived cells exhibit osteochondral potential in vivo. J. Orthop. Res. 9, 465–476 (1997).

    Article  Google Scholar 

  6. Triffitt, J.T. in Principles of Bone Biology (eds. Bilezikian, J.P., Riasz, L.G. & Rodan, G.A.) 39–50 (Academic, San Diego, California 1996).

    Google Scholar 

  7. Aubin, J.E. & Liu, F. in Principles of Bone Biology (eds. Bilezikian, J.P., Riasz, L.G. & Rodan, G.A.) 51– 67 (Academic, San Diego, California 1996).

    Google Scholar 

  8. Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998).

    Article  CAS  Google Scholar 

  9. Onyia, J.E., Clapp, D.W., Long, H. & Hock, J.M. Trabecular and endosteal osteoprogenitor cells as targets for ex-vivo gene transfer. J. Bone Min. Res. 13, 20–30 (1998).

    Article  CAS  Google Scholar 

  10. Hou, Z. et al. Bone tissue-targeted expression of an osteocalcin promoter-reporter construct delivered by total bone marrow adherent cell transplantation. J. Bone Miner. Res. S428 (1997).

  11. Pereira, R.F. et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc. Natl. Acad. Sci. USA 92, 4857– 4861 (1995).

    Article  CAS  Google Scholar 

  12. Byers, P.H. in The Metabolic and Molecular Bases of Inherited Disease 3rd edn. (eds. Scriver C.R., Beaudet A.L., Sly W.S. & Valle D.) 4029 –4077 (McGraw-Hill, New York, 1995 ).

    Google Scholar 

  13. Sillence, D.O. in Principles and Practice of Medical Genetics 3rd edn. (eds. Rimoin D.L., Connor J.M. & Pyeritz R.E.) 2779– 2816 (Churchill Livingstone, New York, 1997).

    Google Scholar 

  14. Marini, J.C. & Gerber, N.L. Osteogenesis imperfecta. Rehabilitation and prospects for gene therapy. J. Am. Med. Assoc. 277, 746–750 (1997).

    Article  CAS  Google Scholar 

  15. Glorieux, F.H. et al. Cyclic administration of Pamidronate in children with severe osteogenesis imperfecta. N. Engl. J. Med. 339, 947–952, 1998.

    Article  CAS  Google Scholar 

  16. Pereira, R.F. et al. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc. Natl. Acad. Sci. USA 95, 1142– 1147 (1998).

    Article  CAS  Google Scholar 

  17. Frost, H.M. in Orthopedic Lectures Vol. III, 59 and 124–130 (Charles C. Thomas Publisher, Springfield, Illinois, 1973 ).

    Google Scholar 

  18. Parsons, V. in Color Atlas of Bone Disease. 85 (Yearbook Medical Publishers Inc., Illinois, 1980).

    Google Scholar 

  19. Jett, S., Ramser, J.R., Frost, H.M. & Villanueva, A.R. Bone Turnover and Osteogenesis Imperfecta. Arch. Pathol. 81, 112–116, 1966.

    CAS  PubMed  Google Scholar 

  20. Koo, W.W.K., Bush, A.J., Walters, J. & Carlson, S.E. Postnatal development of bone mineral status during infancy. J. Amer. Coll. Nutr. 17, 65–70 (1998).

    Article  CAS  Google Scholar 

  21. Hamill, P.V.V. et al. Physical growth: National Center for Health Statistics percentiles. Am. J. Clin. Nutr. 32, 607– 629, 1979.

    Article  CAS  Google Scholar 

  22. Marini, J.C., Bordenick, S., Heavner, G., Rose, S. & Chrousos, G.P. Evaluation of growth hormone axis and responsiveness to growth stimulation of short children with osteogenesis imperfecta. Am. J. Med. Genet. 45, 261– 264 (1993).

    Article  CAS  Google Scholar 

  23. Coccia, P.F. et al. Successful bone-marrow transplantation for infantile malignant osteopetrosis. N. Engl. J. Med. 302, 701 –708 (1980).

    Article  CAS  Google Scholar 

  24. Teitelbaum, S.L., Tondravi, M.M. & Ross, F.P. Osteoclasts, macrophages, and the molecular mechanisms of bone resorption. J. Leukoc. Biol. 61, 381–388 (1997).

    Article  CAS  Google Scholar 

  25. Sanders, J.E. et al. Growth and development following marrow transplantation for leukemia. Blood 68, 1129– 1135 (1986).

    CAS  PubMed  Google Scholar 

  26. Growchow, L.B. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin. Oncol. 20 (4, Suppl 4) 18–25 (1993).

    Google Scholar 

  27. Blazar, B.R. Pretransplant condition with busulfan and cyclophosphamide for nonmalignant diseases. Transplantation 9, 597– 603 (1985).

    Article  Google Scholar 

  28. Hartmann, O. et al. High-dose busulfan and cyclophosphamide with autologous bone marrow transplantation support in advanced malignancies in children: a phase II study. J. Clin. Oncol. 4, 1804– 1810 (1986).

    Article  CAS  Google Scholar 

  29. Constantinou, C. et al. Phenotypic heterogeneity in osteogenesis imperfecta: the mildly affected mother of a proband with a lethal variant has the same mutation substituting cysteine for α-glycine 904 in a type I procollagen gene (COL1A1). Am. J. Hum. Genet. 47, 670–679 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sokolov, B.P., Mays, P.K., Khillan, J.S. & Prockop, D.J. Tissue- and development-specific expression in transgenic mice in the type I procollagen (COL1A1) mini-gene construct with 2.3 kb of the promoter region and 2 kb of the 3'-flanking region. Specificity is independent of putative regulatory sequences of the first intron. Biochemistry 32, 9242–9249 (1993).

    Article  CAS  Google Scholar 

  31. Malech, H.L. et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc. Natl. Acad. Sci. USA 94, 12133–12138 (1997).

    Article  CAS  Google Scholar 

  32. Lajeunesse, D., Busque, L., Menard, P., Brunette, M.G. & Bonny, Y. Demonstration of an osteoblast defect in two cases of human malignant osteopetrosis. J. Clin. Invest. 98, 1835–1842 (1996).

    Article  CAS  Google Scholar 

  33. Fedde, K.N. et al. Amelioration of the skeletal disease in hypophosphatasia by bone marrow transplantation using the alkaline phosphatase-knockout mouse model. Am. J. Hum. Genet. 59, A15 (1996).

    Google Scholar 

  34. Robey, P.G. & Termine, J.D. Human bone cells in vitro. Calcif. Tissue Int. 37, 453– 460 (1985).

    Article  CAS  Google Scholar 

  35. Koo, W.W.K., Masson, L.R. & Walters, J. Validation of accuracy and precision of dual energy x-ray absorptiometry for infants. J. Bone Miner. Res. 10, 1111–1115 (1995).

    Article  CAS  Google Scholar 

  36. Koo, W.W.K., Walters, J., Bush, A.J., Chesny, R.W. & Carlson, S.E. Dual energy x-ray absorptiometry studies of bone mineral status of newborn infants. J. Bone Miner. Res. 11, 997–1002 (1995).

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge J. Marini for discussions throughout this study; and S. Nooner, W. Cabral, B. Hopkins and M. Kinnarney for assistance. We also thank J. Gilbert for his editorial review and J. Johnson for assistance in preparation of this manuscript. This work was supported in part by NHLBI Clinical Investigator Development Award #K08 HL 03266, by Cancer Center Support CORE Grant P30 CA 21765, by the Hartwell Foundation, and by the American Lebanese Syrian Associated Charities (ALSAC).

Author information

Authors and Affiliations

  1. Cell and Gene Therapy Program, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, 38105, Tennessee, USA

    Edwin M. Horwitz, Patricia L. Gordon, Michael Neel, Jeffrey C. Marx & Malcolm K. Brenner

  2. Allegheny University of the Health Sciences, 15th and Vine Streets, Philadelphia, 19102, Pennsylvania, USA

    Darwin J. Prockop & Reed E. Pyeritz

  3. Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Lorraine A. Fitzpatrick

  4. Wayne State University, 4707 St. Antoine Boulevard, Detroit, 48201, Michigan, USA

    Winston W. K. Koo

  5. Shriner's Hospital for Children, 3101 SW Sam Jackson Park Road, Portland, 97201, Oregon, USA

    Michael Sussman

  6. University of Minnesota, 420 Delaware Street, SE, Minneapolis, 55455, Minnesota, USA

    Paul Orchard

Authors
  1. Edwin M. Horwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darwin J. Prockop
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lorraine A. Fitzpatrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Winston W. K. Koo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patricia L. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Neel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Sussman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul Orchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey C. Marx
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Reed E. Pyeritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Malcolm K. Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Horwitz, E., Prockop, D., Fitzpatrick, L. et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5, 309–313 (1999). https://doi.org/10.1038/6529

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/6529

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing