Scientific Article   |    
Expression and Activation of the BMP-Signaling Components in Human Fracture Nonunions
Peter Kloen, MD, PhD; Steven B. Doty, PhD; Eric Gordon, BS; Iván F. Rubel, MD; Marie-Jos纯 Goumans, PhD; David L. Helfet, MD
View Disclosures and Other Information
Investigation performed at The Hospital for Special Surgery, New York, NY

Peter Kloen, MD, PhD
Steven B. Doty, PhD
Eric Gordon, BS
Iván F. Rubel, MD
David L. Helfet, MD
The Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for D.L. Helfet: helfetd@hss.edu

Marie-Josç??oumans, PhD
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from The Netherlands Organization for Scientific Research (MW 902-16-295) and the National Orthopaedic Surgery Fellows Foundation. None of the authors 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, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

J Bone Joint Surg Am, 2002 Nov 01;84(11):1909-1918
5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case


Background: The potential use of bone morphogenetic proteins (BMPs) to promote bone-healing is of great interest to orthopaedic surgeons. Although the complex mechanism leading from the local presence of BMP (whether endogenous or exogenous) to bone formation is increasingly understood, limited information is available as to whether endogenous BMPs, their receptors, or other molecules involved in their signal transduction, such as Smad1, are present or disappear during the development of fracture nonunions. The purpose of the present study was to determine, by immunohistochemical analysis, whether BMPs, BMP receptors, or Smad1 disappear from tissues during the development of a fracture nonunion.

Methods: Twenty-one patients (average age, sixty-one years; range, thirty to eighty-five years) with a delayed union (four patients) or a nonunion (seventeen patients) were included. The average duration of the delayed union or nonunion was twenty-two months (range, 3.5 to 120 months). With use of immunohistochemical analysis, we studied the localization of BMP-2, BMP-4, and BMP-7 and their receptors BMPR-IA, BMPR-IB, and BMPR-II as well as pSmad1. With use of a pSmad1 antibody, we also studied whether the BMP receptors that were expressed were activated.

Results: The immunohistochemical localization of all seven BMP-signaling components was demonstrated in seventeen (81%) of the twenty-one patients. The remaining four patients lacked one or more of the components. Areas of newly formed bone had the highest percentage of positively staining cells, with the staining generally decreasing in areas remote from bone formation. However, even in areas of dense fibrous tissue and in specimens that lacked newly formed bone, immunostaining was still present. The staining patterns showed co-localization of the BMP-2, BMP-4, and BMP-7 proteins with the BMP receptors. The presence of pSmad1 signified the activated state of the BMP receptors, which implies that the BMP signal is transduced inside the cell.

Conclusions and Clinical Relevance: In the present study, nonunions of long duration were noted to have evidence of ongoing BMP-signaling. The profiles of BMP, BMP-receptor, and pSmad1 immunostaining were heterogeneous in this group of patients. The concept that the expression and activation of BMP-signaling components are lacking at the site of delayed unions and nonunions was not supported by the results of the present study.

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


    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

    Related Content
    The Journal of Bone & Joint Surgery
    JBJS Case Connector
    Topic Collections
    Related Audio and Videos
    PubMed Articles
    Clinical Trials
    Readers of This Also Read...
    JBJS Jobs
    LA - Ochsner Health System
    PA - Penn State Milton S. Hershey Medical Center
    OR - The Center - Orthopedic and Neurosurgical Care and Research
    OK - The University of Oklahoma