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Commentary & Perspective | ||||||||
Commentary & Perspective on In this issue of The Journal, Kloen et al. report the results of their use of immunohistochemical analysis to investigate the expression of bone morphogenetic proteins (BMPs) and the activation of BMP-signaling components in human fracture nonunions. The purpose of the study was to determine whether BMPs, BMP receptors, or Smad1 (one of the signal-transducing, receptor-regulated Smad proteins) disappear from the involved tissues during the development of a fracture nonunion and whether their disappearance may contribute to the development of the nonunion. It should be noted that Meyer et al.1 have shown in rats that the expression of BMPs and their receptors is upregulated to peak at one to two weeks after fracture and then is sharply decreased to very low or undetectable levels, in both young rats, in which fractures heal, and in old rats, in which nonunions develop. Specifically, Meyer et al.1 observed that BMP-2, BMP-4, and BMP receptor type IA (BMPR-IA) mRNA levels increased to a peak at one to two weeks after fracture and then fell to very low levels at four to six weeks after fracture. Kloen et al. studied delayed unions or nonunions with an average duration of twenty-two months in twenty-one adult patients. The immunohistochemical localization of BMP-2, BMP-4, BMP-7, and their BMP receptors (BMPR-IA, BMPR-1B, AND BMPR-II) as well as Smad1 were examined. The immunohistochemical localization of all seven of the BMP-signaling components was demonstrated in 81% of the patients, and the staining patterns showed colocalization of the BMPs with their receptors. Thus, the notion that the expression and activation of BMPs and their signaling components are lacking at the sites of delayed unions or nonunions was not supported by the results of this study. However, although delayed unions and nonunions of long duration showed persistent expression of BMPs, their receptors, and signaling components, the authors acknowledged that the concentrations of the BMPs and/or their receptors may not be sufficient to obtain normal healing. These observations raise questions about fundamental differences among critical-sized segmental bone defects2, which heal in the presence of exogenous BMPS but do not heal spontaneously, fractures that heal readily in the presence of endogenous BMPs, and fractures with a propensity for nonunion, which do not heal despite an initial increase in the levels of BMPs and their receptors1 as well as questions about the persistent presence of BMPs in the specimens of nonunion. BMPs facilitate the repair of critical-sized segmental bone defects in experimental animals by stimulating the migration of mesenchymal stem cells from muscle, periosteum, endosteum, and bone marrow into the defect, by the proliferation and differentiation of the mesenchymal stem cells, and by the formation of bone through endochondral ossification. In the last decade, much has been learned about the cellular and molecular mechanisms by which the BMPs elicit bone formation3. Most of these studies have involved critical-sized segmental osteoperiosteal defects in experimental animals4-6. In the experimental operative procedure used to create the osteoperiosteal defect, the soft tissues surrounding the defect are for the most part preserved and there is an abundant source of mesenchymal stem cells, particularly in the surrounding muscle. The experimental defect is also stabilized either with internal fixation or by virtue of the intact radius or tibia when the defect is created in the ulna or fibula, respectively. The conditions that prevail in the human fracture situation are quite different from those in experimental animals and may be as important in determining whether a nonunion will occur as the concentration of endogenous or exogenous BMPs at the fracture site. In comparison with the experimental critical-sized osteoperiosteal defect, the extent of the human fracture may be far greater and its geometry, variable and complex. In response to the chemotactic stimulus of BMPs, mesenchymal stem cells may have too great a distance to migrate from muscle and periosteum to the interstices of the fracture fragments. In open fractures, particularly after débridement, there may be a large loss of muscle and periosteum, resulting in an inadequate supply of mesenchymal stem cells. Finally, as emphasized by Kloen et al., the mechanical stability of the fracture in the clinical situation may be suboptimal. These problems that are associated with fractures with a propensity for nonunion are well known to orthopaedic surgeons. The question is: What advances in the current clinical management of delayed unions or nonunions might potentiate the capacity of endogenous or exogenous BMPs to facilitate the healing of fractures with a propensity for nonunion? *The author did not receive grants or outside funding in support of the research or preparation of this manuscript. He did not receive 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 author is affiliated or associated. References 1. Meyer RA, Meyer MH, Phieffer LS, Banks DM. Delayed union of femoral fractures in older rats: decreased gene expression. BMC Musculoskelet Disord. 2001;2:2. | ||||||||
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