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.

Adipose-Derived Mesenchymal Stem Cell Chondrospheroids Cultured in Hypoxia and a 3D Porous Chitosan/Chitin Nanocrystal Scaffold as a Platform for Cartilage Tissue Engineering

“…Our data revealed a significantly higher expression of HIF-1α at 7 and 14 days in chondrospheroids cultured under hypoxia than in those cultured under normoxia, which explains the higher COL2A1 and aggrecan expression at the same time points. These findings are in line with those obtained by other authors, in which hypoxic conditions were associated with the increased expression of cartilage-related biomarkers and biosynthesis of a glycosaminoglycan-positive matrix in 3D structures [15,49] and the maintenance of the chondrogenic phenotype in chondrocytes [50].…”

Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways

“…For example, in the case of embryonic stem cells, which are at an earlier and less mature developmental stage than adult stem cells, compressive mechanical stress upregulate expression of chondrogenic markers such as collagen type 2, Sox9 and aggrecan, concomitantly with increased YAP/TAZ and RhoA activity ( McKee et al, 2017 ). A specific stimulus that has been reported to maintain differentiated chondrocyte phenotype via YAP activation is hypoxia ( Li H. et al, 2018 ). HIF-1α (hypoxia-inducing factor 1 alpha) is involved in this process, because inhibition of HIF-1α expression decreases YAP activation and downregulates SOX9 expression under hypoxic conditions ( Li H. et al, 2018 ).…”

Development of Magnetic Torque Stimulation (MTS) Utilizing Rotating Uniform Magnetic Field for Mechanical Activation of Cardiac Cells

“…However, significantly less nuclear-localized YAP was seen in cells exposed to hypoxia or a magnetic field alone without generation of torque. Interestingly, hypoxic conditions activate nuclear localization of YAP, which leads to various effects, such as cell proliferation and growth [44,45]. In our experiment, we observed a significant increase in nuclear localization of YAP when torque was generated under hypoxia, while, for hypoxia without torque, nuclear localization of YAP was not observed in cardiomyocytes and fibroblasts.…”