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
Open Access articles citing this article.
Cell Regeneration Open Access 02 February 2023
Journal of Nanobiotechnology Open Access 16 June 2022
Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications
Journal of Biomedical Science Open Access 14 April 2021
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
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).
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).
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).
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).
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).
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).
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).
Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998).
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).
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).
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).
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 ).
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).
Marini, J.C. & Gerber, N.L. Osteogenesis imperfecta. Rehabilitation and prospects for gene therapy. J. Am. Med. Assoc. 277, 746–750 (1997).
Glorieux, F.H. et al. Cyclic administration of Pamidronate in children with severe osteogenesis imperfecta. N. Engl. J. Med. 339, 947–952, 1998.
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).
Frost, H.M. in Orthopedic Lectures Vol. III, 59 and 124–130 (Charles C. Thomas Publisher, Springfield, Illinois, 1973 ).
Parsons, V. in Color Atlas of Bone Disease. 85 (Yearbook Medical Publishers Inc., Illinois, 1980).
Jett, S., Ramser, J.R., Frost, H.M. & Villanueva, A.R. Bone Turnover and Osteogenesis Imperfecta. Arch. Pathol. 81, 112–116, 1966.
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).
Hamill, P.V.V. et al. Physical growth: National Center for Health Statistics percentiles. Am. J. Clin. Nutr. 32, 607– 629, 1979.
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).
Coccia, P.F. et al. Successful bone-marrow transplantation for infantile malignant osteopetrosis. N. Engl. J. Med. 302, 701 –708 (1980).
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).
Sanders, J.E. et al. Growth and development following marrow transplantation for leukemia. Blood 68, 1129– 1135 (1986).
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).
Blazar, B.R. Pretransplant condition with busulfan and cyclophosphamide for nonmalignant diseases. Transplantation 9, 597– 603 (1985).
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).
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).
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).
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).
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).
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).
Robey, P.G. & Termine, J.D. Human bone cells in vitro. Calcif. Tissue Int. 37, 453– 460 (1985).
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).
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).
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).
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
This article is cited by
Cell Regeneration (2023)
LAMP2A regulates the balance of mesenchymal stem cell adipo-osteogenesis via the Wnt/β-catenin/GSK3β signaling pathway
Journal of Molecular Medicine (2023)
Bone marrow mesenchymal stem cells’ osteogenic potential: superiority or non-superiority to other sources of mesenchymal stem cells?
Cell and Tissue Banking (2023)
Current Pharmacology Reports (2023)
Journal of Nanobiotechnology (2022)