Histomorphometric Evidence of Growth Plate Recovery Potential after Fractionated Radiotherapy: AnIn VivoModel

Abstract

This study evaluated the hypothesis that early growth plate radiorecovery is evident by growth rate, histomorphometric and immunohistochemical end points after exposure to clinically relevant fractionated radiation in vivo. Twenty-four weanling 5-week-old male Sprague-Dawley rats were randomized into eight groups. In each animal, the right distal femur and proximal tibia were exposed to five daily fractions of 3.5 Gy (17.5 Gy) with the left leg serving as a control. Rats were killed humanely at 7, 8, 9, 10, 11, 14, 15 and 16 days after the first day of radiation exposure. Quantitative end points calculated included individual zonal and overall growth plate heights, area matrix fraction, OTC-labeled growth rate, chondrocyte clone volume and numeric density, and BrdU immunohistochemical labeling for proliferative index. Transient postirradiation reductions occurred early and improved during observation for growth rate, proliferative indices, transitional/ hypertrophic zone matrix area fraction, proliferative height, and clonal volume. Reserve and hypertrophic zone height remained increased during the period of observation. The current model, using a more clinically relevant fractionation scheme than used previously, shows early evidence of growth plate recovery and provides a model that can be used to correlate temporal changes in RNA and protein expression during the early period of growth plate recovery.

Microarray Analysis of Irradiated Growth Plate Zones following Laser Microdissection Shows Later Importance of Differentially Expressed Genes during Radiorecovery

“…Gradual changes have been noted thereafter, with clones of regenerating chondrocytes clearly identified beginning at 2 weeks after irradiation but continuing to progress over time to a more fully recovered histological appearance and improved growth rate [Damron et al, 2008].…”

Ionizing radiation causes active degradation and reduces matrix synthesis in articular cartilage

“…During the course of radiation therapy (RT) for tumor treatment, the incidental irradiation of non-cancerous (normal) skeletal tissue in joints can be fairly substantial (Konski & Sowers 1996; Luxton et al 2004). While various reports demonstrate the extent and nature of bone and growth plate cartilage damage following exposure (Damron et al 2008; Kwon et al 2008; Pritchard et al 2010; Willey et al 2010; Jia et al 2011; Alwood et al 2012), radiation effects on articular cartilage within the joint structure are undefined and relatively unstudied. Progressive degeneration and arthritis have been reported in various joints exposed to radiation (Kolar et al 1967).…”

Total-body irradiation produces late degenerative joint damage in rats

“…Hypertrophy of growth plate chondrocytes has been shown to occur after irradiation. This presumably contributes to the abnormal bone development and growth observed in childhood cancer survivors after treatment with radiation therapy (Damron et al 2004b; Damron et al 2004a; Margulies et al 2006; Damron et al 2008). Although radiation-induced hypertrophy of articular chondrocytes has not been characterized, several biomarkers of hypertrophy are elevated in human and pig articular chondrocytes after radiation exposure, including increased MMP-13 production and active degradation of GAGs (Willey et al 2013).…”

“…In the musculoskeletal system, the clinical concerns in children have been altered growth, bone fracture, spinal deformity, osteochondroma, and secondary bone malignancies (Leiper et al 1987; Chemaitilly et al 2007; Shido et al 2012). Metaphyseal trabecular bone changes, osteonecrosis of the femoral head, growth plate cartilage manifestations, including slipped capital femoral epiphysis, and platyspondylyl of the spine have been well studied and documented (Kaste et al 2004; Damron et al 2008; Damron et al 2009; Miyazaki et al 2009; Pritchard et al 2010; Mostoufi-Moab et al 2012; Mostoufi-Moab et al 2013). …”