Combination radioprotectors maintain proliferation better than single agents by decreasing early parathyroid hormone-related protein changes after growth plate irradiation.
Our hypothesis was that combinations of radioprotectors would be more effective than individual agents in minimizing the effects of radiation on the growth plate after single-fraction hind-limb irradiation of Sprague-Dawley rats. At 2 days postirradiation, the decrease in parathyroid hormone-related protein and parathyroid hormone receptor 1 expression in the irradiated growth plate transitional and hypertrophic zones was reversed in both of the combination groups but persisted in the groups treated with the individual drugs. By 2 weeks, positive findings unique to the combination-treatment animals included greater mean proliferation in the irradiated growth plate than on the contralateral side, smaller limb length discrepancies, reversal of the increased overall matrix area fraction, and reversal of the usual deficiency in Indian hedgehog staining in the irradiated hypertrophic zone. While all treatments had a positive effect in reversing the decrease in B-cell leukemia 2 protein and coincident increase in Bax previously observed 2 weeks postirradiation, the two combination groups had a more robust effect. Combinations of radioprotectors may achieve their beneficial additive effects in the growth plate by decreasing the usual early drop in parathyroid hormone-related protein and parathyroid hormone receptor 1 after irradiation, resulting in a cascade of parathyroid hormone-related protein-mediated events.
Department of Orthopedic Surgery, SUNY Upstate Medical University, Syracuse, New York 13210, USA. damront@upstate.edu
Timothy A
TA
Damron
Jason A
JA
Horton
Asghar
A
Naqvi
Richard M
RM
Loomis
Bryan S
BS
Margulies
Judith A
JA
Strauss
Cornelia E
CE
Farnum
Joseph A
JA
Spadaro
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005121:Extremities / Q000033:anatomy & histology / Q000528:radiation effects; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D007150:Immunohistochemistry; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D013997:Time Factors
D044162:Parathyroid Hormone-Related Protein; D011837:Radiation-Protective Agents; D018016:Receptors, Parathyroid Hormone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases