The effect of inhibition of heat-shock proteins on thiram-induced tibial dyschondroplasia

Abstract

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.

WITHDRAWN: Evaluation of clinical, pathological and genetic indicators in chickens with thiram-induced tibial dyschondroplasia

“…VEGF mRNA transcripts were increased significantly in TD-affected chicks [29]. Dan et al [6] and Genin et al [24] found that TD endorsed the change in the VEGF signaling pathway and in abnormal chondrocyte differentiation. Wnt4 is a secreted protein; some research has shown that Wnt4 from osteoblasts significantly The results are expressed in arbitrary units, and data represent the mean ± SE.…”

“…Shahzad et al [8] showed that birds in the TD group have developed a lesion filled with cartilaginous material by day 10; when the thiram supplement was stopped, the lesion started decreasing, and the growth plate underwent a recovery process and was replaced by bone by day 14 post-hatch [9]. Genin et al [24] showed that the growth plate width and lameness had no change in normal chickens, while in TD-afflicted chickens, an enlarged growth plate, TD lesions, and lameness occurred.…”

Salvia Miltiorrhiza Reinstates Growth Plate Width, Reduces Liver Oxidative Stress and Toxicity in Avian Tibial Dyschondroplasia

“…SM treatment significantly restored ALP level in blood serum. ALP level is deficient in TD but its level was restored to normal level both in affected area and in blood after the treatment with SM with concurrent resolution of TD (Nabi et al, 2016a;Genin et al, 2012;Shahzad et al, 2014).…”

“…ALP measurement in serum is primary marker of bone formation and TD is associated with significant decreased ALP level (Genin et al, 2012). SM treatment significantly restored ALP level in blood serum.…”

Earlier hatching time predisposes Cobb broiler chickens to tibial dyschondroplasia

“…TD remains an extremely common skeletal abnormality in commercial broiler chickens worldwide (Pines et al, 2005;Dinev et al, 2012;Genin et al, 2012). TD is described as one of the most prevalent leg weakness conditions seen in modern broilers (Yalçin et al, 2007), and lesions have been found to be present in 30% of broiler flock (Crespo and Shivaprasad, 2011;Shahzad et al, 2015).…”