Role of pentoxifylline in preventing radiation damage to epiphyseal growth plate chondrocytes.
Radiation therapy plays an important role as part of multimodality treatment for a number of childhood malignancies. The damaging effects of radiation on bone formation in children have been well documented. Recent work suggests that the postirradiation increase in cytosolic calcium is probably responsible for the deleterious effects of radiation on growth plate chondrocytes because it causes a specific suppression of the mitogen PTHrP. Using an in vitro model of avian growth plate chondrocytes, this study demonstrates that pentoxifylline is effective in increasing basal PTHrP mRNA levels and partially preventing the radiation-induced decrease in PTHrP mRNA. This effect of pentoxifylline is probably due to its ability to lower basal levels of cytosolic calcium and the radiation-induced increase in cytosolic calcium in chondrocytes. Pentoxifylline also prevented the radiation-induced decreases in [3H]thymidine uptake and BCL2 and PTHrP receptor mRNA levels in chondrocytes. The effects of pentoxifylline appear to be specific for the PTHrP signaling pathway because it did not alter basal TGFB mRNA levels or TGFB mRNA expression in irradiated chondrocytes. The results of the current study suggest that by decreasing basal cytosolic calcium levels and curtailing the radiation-induced increase in cytosolic calcium levels in chondrocytes, pentoxifylline is able to sustain PTHrP signaling in chondrocytes and maintains the proliferative signal that is necessary to prevent chondrocytes from undergoing apoptosis.
Pateder
Dhruv B
DB
Department of Orthopaedic Surgery, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Sheu
Tzong Jen
TJ
O'Keefe
Regis J
RJ
Puzas
J Edward
JE
Schwarz
Edward M
EM
Constine
Louis S
LS
Okunieff
Paul
P
Rosier
Randy N
RN
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002642:Chick Embryo; D019902:Chondrocytes / Q000187:drug effects* / Q000528:radiation effects; D003600:Cytosol / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects*; D019254:Genes, bcl-2 / Q000528:radiation effects; D006132:Growth Plate / Q000187:drug effects* / Q000528:radiation effects; D044162:Parathyroid Hormone-Related Protein; D010431:Pentoxifylline / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D010431:Pentoxifylline; D002118:Calcium