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The Journal of Bone and Joint Surgery (American) 84:1909-1918 (2002)
© 2002 The Journal of Bone and Joint Surgery, Inc.

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-José Goumans, PhD and David L. Helfet, MD

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{at}hss.edu

Marie-José Goumans, 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).

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.


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