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Hypoxia, Hypoxia-Inducible Factor-1 (HIF-1), and Heat-Shock Proteins in Tibial Dyschondroplasia

Institute of Animal Sciences, Volcani Center, Bet Dagan 50250, Israel

¹ Corresponding author: pines{at}agri.huji.ac.il

Tibial dyschondroplasia (TD) is one of the most prevalent skeletal abnormalities in avian species; it causes economic losses and is an animal welfare problem. It has been hypothesized that the absence of vasculature in the lesion of the TD growth plates at the ends of the long bones is involved in the etiology of the disease. We evaluated the hypoxia status of normal and thiram-induced TD growth plates by immunostaining the protein adducts after pimonidazole hydrochloride administration. In addition, we evaluated the expression of hypoxia-inducible factor-1 (HIF-1), the major regulator of the hypoxic response that is essential for chondrogenesis, and that of heat-shock proteins (Hsp) downstream from HIF-1. We demonstrated that, in contrast to the normal growth plates, those afflicted by TD were hypoxic. A major increase in hypoxia was observed in the proliferative, hypertrophic, and calcified zones. In the normal growth plate, HIF-1 was expressed in chondrocytes of the articular cartilage and of the maturation zone, whereas in cases of TD, HIF-1 was also expressed in chondrocytes below the lesion. The expression level of HIF-1 was related to the severity of the disease, but was independent of its cause; the same pattern of expression was observed in growth plates of chicks selected for a high incidence of TD. No differentiation-dependent expression of HIF-1 was observed in response to hypoxia, as demonstrated by the use of primary cultures of growth plate chondrocytes. In the normal growth plates, Hsp90 and Hsp70 were localized to the maturation zone. More cells expressed both Hsp in the TD lesion. In conclusion, we demonstrated that the TD growth plate, in contrast to the normal one, is hypoxic, probably because of the lack of vascularization. Hypoxia leads to an increase in the transcription factor HIF-1, causing increases in the levels of Hsp90 and Hsp70.

Key Words: heat-shock protein • alkaline phosphatase • chondrocyte • growth plate