The effect of inhibition of heat-shock proteins on thiram-induced tibial dyschondroplasia.
Tibial dyschondroplasia (TD) is a skeletal abnormality that can cause economic losses and animal welfare concerns. Thiram-induced TD is characterized by enlarged, unvascularized growth plates, low levels of the vascular endothelial growth factor receptor Flk-1, abnormal chondrocyte differentiation, and lameness. Recently we reported the involvement of heat-shock protein 90 (Hsp90) in chondrocyte differentiation and growth-plate vascularization. Inhibition of Hsp90 activity in thiram-induced TD resulted in increased Flk-1 levels, re-instated normal growth-plate angiogenesis and morphology, and abrogated lameness. In the present study, we evaluated the efficacy of various concentrations of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90 activity, in preventing growth-plate histopathology and lameness in TD-affected chicks. Low doses of 17-DMAG (2 injections, each of 100 or 300 μg) did not prevent TD development even though Flk-1 levels were restored, which suggests that Flk-1 is not the only rate-limiting factor in growth-plate angiogenesis. High doses of 17-DMAG (2 injections, each of 600 or 900 μg) prevented BW loss, decreased the TD score, reduced lesion width, restored proper chondrocyte differentiation, increased blood vessel invasion, and eliminated lameness. To assess the specificity of Hsp90, we evaluated the efficacy of the flavonoid quercetin, an inhibitor of Hsp70 synthesis, in preventing TD development; it decreased Hsp70 levels but not those of Hsp90 in the control growth plates and prevented upregulation of Hsp70 in the TD-affected growth plates. Dietary quercetin (at 100 or 500 ppm) did not prevent the hypoxia that is characteristic of the TD-affected growth plate or development of thiram-induced TD and lameness. The present results demonstrate the specificity and the major role of Hsp90 in chondrocyte differentiation and growth-plate vascularization. In contrast to the anti-angiogenic effect of 17-DMAG observed in mammals, inhibition of Hsp90 activity in the unvascularized TD-affected growth plates resulted in activation of the angiogenic switch and restored normal growth-plate morphology.
Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel.
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Genin
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Hasdai
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Shinder
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Pines
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D010009:Osteochondrodysplasias / Q000139:chemically induced / Q000473:pathology / Q000662:veterinary*; D011201:Poultry Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011794:Quercetin / Q000494:pharmacology; D013893:Thiram / Q000009:adverse effects*
D016227:Benzoquinones; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D013893:Thiram; D011794:Quercetin