Effects of radiation therapy on chondrocytes in vitro.
The negative irradiation complications of growth loss leading to limb length asymmetry and pathological fracture incurred following radiation therapy in pediatric patients has led to a renewed interest in understanding the specific effects of irradiation on the growth plate and the surrounding bone. In the present report, we examined the radiation therapy effects on primary rat growth cartilage chondrocytes in order to determine the chondrocyte radiosensitivity relative to other bone cell constituents and tumor cells, the postirradiation temporal progression of radiation-induced alterations in chondrocyte function, and the time course for the functional restoration of chondrocyte pathways that drive the eventual recovery in growth function. We employed an in vitro primary rat costochondral growth cartilage cell culture model system to evaluate the radiation therapy effects on proliferative chondrocytes using serial radiation doses (0-20 Gy) that are well within the clinically relevant range. Following irradiation, all of the following occurred in a dose-dependent manner: proliferation decreased, cytotoxicity increased, several markers of apoptosis increased, markers of radiation-induced cellular differentiation increased, and cell synthetic activity was disturbed. Alterations in proliferation, cell death, and induction of apoptosis are likely due to a transient radiation-induced derangement of the parathyroid hormone-related protein-Indian hedgehog proliferation-maturation pathway. Alterations in cellular differentiation and cell synthetic activity are novel observations for chondrocytes. Further, these results correspond very well to our previous work in an in vivo Sprague-Dawley rat model, making this model particularly relevant to researching the radiation therapy effects on longitudinal growth.
Margulies
B S
BS
Department of Orthopedic Surgery, State University of New York, Upstate Medical University, 505 Irving Avenue, Syracuse, NY 13210, USA. margulib@upstate.edu
Horton
J A
JA
Wang
Y
Y
Damron
T A
TA
Allen
M J
MJ
D000469:Alkaline Phosphatase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D002356:Cartilage / Q000166:cytology / Q000254:growth & development* / Q000528:radiation effects*; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D002454:Cell Differentiation / Q000502:physiology / Q000528:radiation effects*; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D020219:Chondrogenesis / Q000502:physiology / Q000528:radiation effects*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006132:Growth Plate / Q000503:physiopathology / Q000528:radiation effects; D053823:Hedgehog Proteins; D019899:Paracrine Communication / Q000502:physiology; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism / Q000528:radiation effects; D011829:Radiation Dosage; D011878:Radiotherapy / Q000009:adverse effects; D051381:Rats; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D015534:Trans-Activators / Q000378:metabolism / Q000528:radiation effects
D017077:Culture Media, Conditioned; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D015534:Trans-Activators; D000469:Alkaline Phosphatase