The Journal of Bone and Joint Surgery (American) 85:1243-1254 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.
Gene Expression in Older Rats with Delayed Union of Femoral Fractures
Ralph A. Meyer Jr, PhD,
Martha H. Meyer, MS,
Mark Tenholder, MD,
Sharon Wondracek, BS,
Ruth Wasserman, MS and
Patricia Garges, BS
Investigation performed at the Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Carolinas Medical Center, Charlotte, North Carolina
Ralph A. Meyer Jr., PhD
Martha H. Meyer, MS
Mark Tenholder, MD
Sharon Wondracek, BS
Ruth Wasserman, MS
Patricia Garges, BS
Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232-2861. E-mail address for R.A. Meyer Jr.: rmeyer{at}carolinas.org
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the Orthopaedic Research and Education Foundation (R.A.M. Jr. and M.T.) and the American Physiological Society (R.W.). 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.
Background: Fracture-healing slows with age. While six-week-old rats regain normal bone biomechanics at four weeks after a fracture, one-year-old rats require more than twenty-six weeks. The objective of this study was to examine the possible role of altered mRNA gene expression in this delayed union.
Methods: Closed midshaft femoral fractures were created in six-week-old and one-year-old Sprague-Dawley female rats. The animals were killed at zero-time (unfractured) or at 0.4, one, two, three, four, or six weeks after the fracture. mRNA levels were measured by reverse transcription-polymerase chain reaction in the fracture callus for twenty-seven matrix, cytokine, and cytokine-receptor genes for the seven animals per time-point per age-group.
Results: The younger rats healed radiographically by four weeks after the fracture, whereas none of the older rats had healed by the sixth week. Despite the difference in healing rates, the levels of mRNA gene expression, in general, followed the same pattern in both age-groups. The mRNA expression levels increased to a peak at one to two weeks after the fracture and then decreased to very low or undetectable levels at four and six weeks after the fracture for both age-groups. Significantly lower levels of mRNA for Indian hedgehog (Ihh) and bone morphogenetic protein-2 (BMP-2) were detected in the fracture calluses of the older rats (p < 0.01 and p < 0.05, respectively).
Conclusions: All genes studied were up-regulated by the fracture in both age-groups. Thus, the failure of the older rats to heal promptly was not due to the lack of expression of any of the studied genes. The increase in mRNA for Ihh and BMP-2 in the older rats was smaller than that in the younger rats, which may contribute to slower fracture repair. The return of mRNA gene expression to baseline in the older rats prior to healing may contribute to the delayed union. The slower healing response of the older rats did not stimulate a negative-feedback increase in the mRNA expression of stimulatory cytokines.
Clinical Relevance: These data underscore the complexity of regulation of fracture-healing. Cytokine stimulation by the fracture may last for a constant length of time regardless of whether the bone actually unites. Alternatively, one set of cytokines may drive soft callus formation, while another set stimulates bridging callus formation. These data suggest that, if cytokines were administered to enhance bone repair, the age and metabolic status of the patient could influence the optimal timing of the administration.
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