This Article Full Text Full Text (PDF) CME: Take the activities for this article: Pediatrics Test 12: Spring 2007 (publication date May 15, 2007; expiration ... CME 1: January, February, March 2007 (publication date April 5, 2007; expir... Letters to the Editor: Submit a response Letters to the Editor: View responses Alert me when this article is cited Alert me when Letters to the Editor are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaplan, F. S. Articles by Emerson, S. G. Search for Related Content PubMed PubMed Citation Articles by Kaplan, F. S. Articles by Emerson, S. G. Related Collections Pediatrics Social Bookmarking                   What's this?

Hematopoietic Stem-Cell Contribution to Ectopic Skeletogenesis

¹ Center for Research in Fibrodyplasia Ossificans Progressiva and Related Disorders, Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, 424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6081. E-mail address for F.S. Kaplan: frederick.kaplan{at}uphs.upenn.edu
² Division of Hematology-Oncology, Department of Medicine, Hospital of The University of Pennsylvania, Maloney-510, 3400 Spruce Street, Philadelphia, PA 19104
³ Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010

Investigation performed at the Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders, Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and the Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Cali Family Fibrodysplasia Ossificans Progressiva Research Endowment, the Weldon Family Fibrodysplasia Ossificans Progressiva Research Endowment, the International Fibrodysplasia Ossificans Progressiva Association, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, the Orthopaedic Research and Education Foundation Clinician-Scientist Award, and National Institutes of Health Grant RO1-AR41916. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Methods: We employed both careful clinical observation and in vivo murine transplantation studies to more precisely determine the contribution of hematopoietic cells to ectopic skeletogenesis. We identified a patient with fibrodysplasia ossificans progressiva who had undergone bone marrow transplantation for the treatment of intercurrent aplastic anemia twenty-five years earlier and investigated whether the clinical course of the fibrodysplasia ossificans progressiva had been influenced by bone marrow replacement or immunosuppression, or both. In complementary studies, we transplanted hematopoietic stem cells from constitutively expressing LacZ transgenic mice to identify the contribution of hematopoietic cells to BMP4-induced heterotopic ossification, a histopathologic model of fibrodysplasia ossificans progressiva.

Results: We found that replacement of hematopoietic cells was not sufficient to prevent ectopic skeletogenesis in the patient with fibrodysplasia ossificans progressiva but pharmacologic suppression of the apparently normal donor immune system following transplantation in the new host modulated the activity of the fibrodysplasia ossificans progressiva and diminished the expression of skeletal ectopia. In complementary murine transplantation studies, we found that cells of hematopoietic origin contributed to the early inflammatory and late marrow-repopulating stages of BMP4-induced heterotopic ossification but were not represented in the fibroproliferative, chondrogenic, or osteogenic stages of heterotopic ossification. Interestingly, both recombinant human BMP4 induction in an animal model and the dysregulated BMP signaling pathway in a patient with fibrodysplasia ossificans progressiva were sufficient to recruit at least two populations of cells, one of hematopoietic origin and at least one of non-hematopoietic origin, that contribute to the formation of an ectopic skeleton.

Conclusions: Taken together, these findings demonstrate that bone marrow transplantation did not cure fibrodysplasia ossificans progressiva in the patient in this study, most likely because the hematopoietic cell population is not the site, or at least not the dominant site, of the intrinsic dysregulation of the BMP signaling pathway in fibrodysplasia ossificans progressiva. However, following transplantation of bone marrow from a presumably normal donor, immunosuppression of the immune system appeared to ameliorate activation of ectopic skeletogenesis in a genetically susceptible host. Thus, cells of hematopoietic origin may contribute to the formation of an ectopic skeleton, although they are not sufficient to initiate the process alone.

Clinical Relevance: Therapeutic regulation of hematopoietic and osteogenic cell populations involved in fibrodysplasia ossificans progressiva lesions holds promise for treatment of fibrodysplasia ossificans progressiva and possibly other disorders of heterotopic ossification.

CiteULike    Connotea    Del.icio.us    Facebook    Technorati    Twitter    What's this?

This article has been cited by other articles:

				C. A. Cipriano, S. G. Pill, and M. A. Keenan Heterotopic Ossification Following Traumatic Brain Injury and Spinal Cord Injury J. Am. Acad. Ortho. Surg., November 1, 2009; 17(11): 689 - 697. [Abstract] [Full Text] [PDF]

				T. Fukuda, M. Kohda, K. Kanomata, J. Nojima, A. Nakamura, J. Kamizono, Y. Noguchi, K. Iwakiri, T. Kondo, J. Kurose, et al. Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva J. Biol. Chem., March 13, 2009; 284(11): 7149 - 7156. [Abstract] [Full Text] [PDF]

				V. Y. Lounev, R. Ramachandran, M. N. Wosczyna, M. Yamamoto, A. D.A. Maidment, E. M. Shore, D. L. Glaser, D. J. Goldhamer, and F. S. Kaplan Identification of Progenitor Cells That Contribute to Heterotopic Skeletogenesis J. Bone Joint Surg. Am., March 1, 2009; 91(3): 652 - 663. [Abstract] [Full Text] [PDF]

				H. Hosalkar, J. Hsu, N. K. Pandya, and M. A. Keenan What's New in Orthopaedic Rehabilitation J. Bone Joint Surg. Am., October 1, 2008; 90(10): 2301 - 2311. [Full Text] [PDF]

Letters to the Editor:

Stanford University Libraries' HighWire Press (TM) assists in the publication of JBJS Online.
Copyright © 2007 by The Journal of Bone and Joint Surgery, Inc. Online ISSN: 1535-1386.
The Journal of Bone and Joint Surgery®, JBJS®, JB&JS®, and eJBJS® are registered in the U.S. Patent and Trademark Office.