Institute of Animal Sciences, The Volcani Center, P.O. Box 6, Bet Dagan, 50250, Israel.
Am J Physiol Regul Integr Comp Physiol. 2011 Jul;301(1):R140-7. doi: 10.1152/ajpregu.00134.2011. Epub 2011 May 11.
Thiram-induced tibial dyschondroplasia (TD) and vitamin-D deficiency rickets are avian bone disorders of different etiologies characterized by abnormal chondrocyte differentiation, enlarged and unvascularized growth plates, and lameness. Heat-shock protein 90 (Hsp90) is a proangiogenic factor in mammalian tissues and in tumors; therefore, Hsp90 inhibitors were developed as antiangiogenic factors. In this study, we evaluated the association between Hsp90, hypoxia, and angiogenesis in the chick growth plate. Administration of the Hsp90 inhibitor to TD- and rickets-afflicted chicks at the time of induction resulted in reduction in growth-plate size and, contrary to its antiangiogenic effect in tumors, a major invasion of blood vessels occurred in the growth plates. This was the result of upregulation of the VEGF receptor Flk-1, the major rate-limiting factor of vascularization in TD and rickets. In addition, the abnormal chondrocyte differentiation, as characterized by collagen type II expression and alkaline phosphatase activity, and the changes in hypoxia-inducible factor-1α (HIF-1α) in both disorders were restored. All these changes resulted in prevention of lameness. Inhibition of Hsp90 activity reduced growth-plate size, increased vascularization, and mitigated lameness also in TD chicks with established lesions. In summary, this is the first reported demonstration of involvement of Hsp90 in chondrocyte differentiation and growth-plate vascularization. In contrast to the antiangiogenic effect of Hsp90 inhibitors observed in mammals, inhibition of Hsp90 activity in the unvascularized TD- and rickets-afflicted chicks resulted in activation of the angiogenic switch and reinstated normal growth-plate morphology.
Thiram 诱导的胫骨软骨发育不良（TD）和维生素 D 缺乏性佝偻病是两种不同病因的禽类骨骼疾病，其特征为软骨细胞分化异常、生长板增大且无血管化以及跛行。热休克蛋白 90（Hsp90）是哺乳动物组织和肿瘤中的促血管生成因子；因此，开发了 Hsp90 抑制剂作为抗血管生成因子。在这项研究中，我们评估了 Hsp90、缺氧和血管生成在鸡生长板中的关系。在诱导 TD 和佝偻病鸡时给予 Hsp90 抑制剂，会导致生长板大小减小，与肿瘤中的抗血管生成作用相反，血管大量侵入生长板。这是由于 VEGF 受体 Flk-1 的上调所致，Flk-1 是 TD 和佝偻病血管生成的主要限速因素。此外，异常的软骨细胞分化，如 II 型胶原表达和碱性磷酸酶活性的改变，以及两种疾病中缺氧诱导因子-1α（HIF-1α）的改变，都得到了恢复。所有这些变化都导致了跛行的预防。Hsp90 活性的抑制减少了生长板的大小，增加了血管生成，并减轻了跛行，即使在已发生病变的 TD 鸡中也是如此。总之，这是首次报道 Hsp90 参与软骨细胞分化和生长板血管生成的研究。与在哺乳动物中观察到的 Hsp90 抑制剂的抗血管生成作用相反，在未血管化的 TD 和佝偻病鸡中抑制 Hsp90 活性会导致血管生成开关的激活，并恢复正常的生长板形态。
