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Sequential Histomorphometric Analysis of the Growth Plate Following Irradiation with and without Radioprotection

Investigation performed at the Musculoskeletal Research Laboratory of the Department of Orthopedic Surgery, Institute for Human Performance at State University of New York Upstate Medical University, Syracuse, New York

Timothy A. Damron, MD
Bryan S. Margulies, MS
Judith A. Strauss, BS
Joseph A. Spadaro, PhD
Musculoskeletal Research Laboratory of the Department of Orthopedic Surgery, Institute for Human Performance at State University of New York Upstate Medical University, 505 Irving Avenue, Syracuse, NY 13210. E-mail address for T.A. Damron: damront{at}upstate.edu

Kate O'Hara, BS
Cornelia E. Farnum, DVM, PhD
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the National Institutes of Health/National Cancer Institute. 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: The availability of radioprotectant drugs that selectively protect normal cells but not tumor cells has rekindled interest in the effects of irradiation on the growth plate. The purpose of the present study was to quantitatively examine the sequential histomorphometric effects of irradiation and pretreatment with a free radical scavenger radioprotectant, amifostine, on the growth plate over time.

Methods: Sixty four-week-old male Sprague-Dawley rats were randomized into five groups of twelve animals that were to be killed at 0.5, one, two, three, or four weeks after irradiation. One-half of the animals also received amifostine (100 mg/kg) prior to irradiation. In all animals, the right knee was treated with a single 17.5-Gy dose of radiation. End points were assessed with quantitative histomorphometric analysis of the growth plate, BrdU labeling for evidence of proliferation, evaluation of chondroclast cellularity, and determination of growth rates by means of oxytetracycline labeling.

Results: The mean lengths of the femur, tibia, and hind limb continued to increase at each time-interval following treatment, but by one week the mean limb length was 4% less on the irradiated side than on the control side, and this difference remained significant for four weeks (p < 0.05). The proximal tibial growth rate decreased during the first week to 18% of the control level. Nevertheless, growth continued even at the earliest time-periods, began to return toward normal at two weeks, and ultimately returned to at least 80% of normal by four weeks after irradiation. The area fraction of matrix in the hypertrophic zone increased initially and returned to control levels at three and four weeks. The administration of the radioprotectant resulted in significant increases in growth, growth rate, growth plate height, hypertrophic zonal height, and chondroclast profiles compared with the values for limbs in which irradiation had not been preceded by treatment with amifostine.

Conclusions: We found an initially profound but transient direct inhibitory effect of irradiation on growth plate chondrocytes. Recovery of growth plate function after irradiation corresponded temporally with the appearance of newly formed islands of proliferating chondrocytes. Accumulation of matrix led to a transient increase in overall growth plate height, which was most pronounced in the hypertrophic zone. This was due, in part, to the sensitivity of chondroclasts to irradiation. The radioprotectant amifostine reduced these effects on growth rate, growth plate height, matrix accumulation, and limb length.

Clinical Relevance: The transient effects of irradiation on the growth plate are reduced by a clinically utilized radioprotectant drug. Use of radioprotectants may have potential for reducing the damaging effects of irradiation on the growth plate while preserving the desirable effects of irradiation on tumors.

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