Hypoxia promotes maintenance of the chondrogenic phenotype in rat growth plate chondrocytes through the HIF-1α/YAP signaling pathway.

Abstract

The Hippo-yes-associated protein (YAP) signaling pathway was previously identified to serve an important role in controlling chondrocyte differentiation and post-natal growth. Growth plate cartilage tissue is avascular, and hypoxia-inducible factor (HIF)-1α is essential for chondrocytes to maintain their chondrogenic phenotype in a hypoxic environment. In the present study, the role of hypoxia and HIF-1α in the regulation of YAP in chondrocytes was investigated. The data demonstrated that hypoxia promoted the maintenance of the chondrogenic phenotype, HIF-1α expression and YAP activation in chondrocytes in a time-dependent manner. Hypoxia promoted YAP activation in a Hippo-independent manner. Inhibiting the expression of HIF-1α decreased the activation of YAP and downregulated the expression of sex-determining region-box 9 protein (SOX9) under hypoxic conditions, while the upregulation of HIF-1α by cobalt chloride promoted the expression and nuclear translocation of YAP and upregulated the expression of SOX9 and collagen II chain under normoxic conditions. In addition, inhibition of YAP expression under hypoxia did not affect the expression of the HIF-1α signaling pathway, but inhibited the up-regulation of SOX9 expression caused by hypoxia. In addition, reoxygenation following hypoxia inhibited the activation of YAP caused by hypoxia in chondrocytes, whereas the upregulation of SOX9 and collagen II chain also appeared to be inhibited. In conclusion, the results of the present study demonstrated that hypoxia promoted YAP activation via HIF-1α. Therefore, the HIF-1α/YAP signaling axis may serve an important role in controlling growth plate chondrocyte differentiation and the maintenance of the chondrogenic phenotype in growth plate chondrocytes.