0
Scientific Articles   |    
Hematopoietic Stem-Cell Contribution to Ectopic Skeletogenesis
Frederick S. Kaplan, MD1; David L. Glaser, MD1; Eileen M. Shore, PhD1; Robert J. Pignolo, MD, PhD1; Meiqi Xu, BS1; Yi Zhang, MD, PhD2; David Senitzer, PhD3; Stephen J. Forman, MD3; Stephen G. Emerson, MD, PhD2
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@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
View Disclosures and Other Information
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.
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

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 Feb 01;89(2):347-357. doi: 10.2106/JBJS.F.00472
5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case

Abstract

Background: Fibrodysplasia ossificans progressiva is a rare genetic disorder of ectopic skeletogenesis associated with dysregulation of bone morphogenetic protein (BMP) signaling. Hematopoietic cells have been implicated in the ectopic skeletogenesis of fibrodysplasia ossificans progressiva, and their replacement has been postulated as a possible cure. However, the definitive contribution of hematopoietic cells to the pathogenesis of ectopic skeletogenesis remains obscure.

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.

Figures in this Article
    Sign In to Your Personal ProfileSign In To Access Full Content
    Not a Subscriber?
    Get online access for 30 days for $35
    New to JBJS?
    Sign up for a full subscription to both the print and online editions
    Register for a FREE limited account to get full access to all CME activities, to comment on public articles, or to sign up for alerts.
    Register for a FREE limited account to get full access to all CME activities
    Have a subscription to the print edition?
    Current subscribers to The Journal of Bone & Joint Surgery in either the print or quarterly DVD formats receive free online access to JBJS.org.
    Forgot your password?
    Enter your username and email address. We'll send you a reminder to the email address on record.

     
    Forgot your username or need assistance? Please contact customer service at subs@jbjs.org. If your access is provided
    by your institution, please contact you librarian or administrator for username and password information. Institutional
    administrators, to reset your institution's master username or password, please contact subs@jbjs.org

    References

    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
    CME Activities Associated with This Article
    Submit a Comment
    Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
    Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

    * = Required Field
    (if multiple authors, separate names by comma)
    Example: John Doe





    Frederick S. Kaplan, M.D.
    Posted on April 24, 2007
    Bone marrow Transplantation Does Not Cure FOP
    The University of Pennsylvania School of Medicine, Philadelphia, PA

    We did indeed cite Dr. Altschuler's contribution(1) in alerting the fibrodysplasia ossificans progressiva (FOP) community to this patient. However, the important theoretical point which we explored and highlighted in our article(2), is that bone marrow transplantation did not cure FOP in this patient, while immunosuppression effectively ameliorated symptoms.

    References:

    1. Altschuler EL. Letters to the editor:Bone marrow transplantation in a patient with fibrodysplasia. Clin Orthop Rel Res.2004;422:277-278.

    2. Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am.2007;89:347-357.

    Eric L. Altschuler, M.D., Ph.D.
    Posted on April 06, 2007
    Appreciation of a Bone Marrow Transplant Patient with Fibrodysplasia Ossificans Progressiva
    Department of Physical Medicine & Rehabilitation, University of Medicine & Dentistry of New Jersey

    To The Editor:

    I read with great interest the recent paper by Kaplan et al.(1) describing the disease course of a patient with fibrodysplasia ossificans progressiva (FOP) who had a bone marrow transplant(2) twenty-five years previously for aplastic anemia. However, I was quite surprised at the incomplete (and erroneus) manner in which Kaplan et al. noted that the patient “first came to the attention of the fibrodysplasia ossificans progressiva community at the age of thirty-five”, and so I write to set the record straight.

    The patient came to the attention of the fibrodysplasia ossificans community due initially and crucially to my efforts. The patient was lost for a decade, and from a research point of view, neither the patient’s hematologists, nor any one in the FOP community, or anyone else(3), cited the report(2) until I did(4). I went to considerable lengths to alert and exhort the transplant physicians to follow-up this case.

    After transplantation the patient had both acute and chronic graft-versus-host disease which was successfully treated with prednisone, cyclosporine and methotrexate for 14 years. This time period of treatment of graft-versus-host disease coincided with a cessation of FOP disease activity—sui generis(1) and returned after the drugs were stopped. These medicines have significant side effects and toxicities; also, as Kaplan et al.(1) note, the patient had a “non-FOP” hematopoietic system so it may not be possible to generalize treatment with this drug regimen to other afflicted patients.

    Nevertheless, we may be cautiously and guardedly optimistic that FOP has been moved out of the untreatable column.

    The author did not receive any outside funding or grants in support of his research for or preparation of this work. Neither he nor a member of his immediate family 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 author, or a member of his immediate family, is affiliated or associated .

    References:

    1. Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am. 2007;89:347-57.

    2. Spruce WE, Forman SJ, Blume KG, Farbstein MJ, Scott EP, Wolf JL, Krance R. Successful second bone marrow transplantation in a patient with myositis ossificans progressiva and aplastic anemia. Am J Pediatr Hematol Oncol. 1983;5:337 -40.

    3. http://scientific.thomson.com/products/sci/ (accessed April 6, 2007).

    4. Altschuler EL. Letters to the editor: Bone marrow transplantation in a patient with fibrodysplasia. Clin Orthop Relat Res.2004; 422:277 -8.

    Related Content
    The Journal of Bone & Joint Surgery
    JBJS Case Connector
    Topic Collections
    Related Audio and Videos
    Clinical Trials
    Readers of This Also Read...
    JBJS Jobs
    04/16/2014
    CT - Yale University School of Medicine
    03/19/2014
    VA - VIRGINIA COMMONWEALTH UNIVERSITY MEDICAL CENTER
    04/02/2014
    WV - Charleston Area Medical Center
    03/26/2014
    MA - Boston University Orthopedic Surgical Associates