CHRDL2 activates the PI3K/AKT pathway to ameliorate glucocorticoid-induced damages to bone microvascular endothelial cells (BMECs).

ABSTRACT

Steroid-induced avascular necrosis of the femoral head (ANFH) is characterized by the death of bone tissues, leading to the impairment of normal reparative processes within micro-fractures in the femoral head. Glucocorticoid (GCs)-induced bone microvascular endothelial cell (BMEC) damage has been reported to contribute to ANFH development. In this study, differentially expressed genes (DEGs) between necrosis of the femoral head (NFH) and normal samples were analyzed based on two sets of online expression profiles, GSE74089 and GSE26316. Chordin-like 2 (CHRDL2) was found to be dramatically downregulated in NFH samples. In GCs-stimulated BMECs, cellular damages were observed alongside CHRDL2 down-regulation. GCs-caused cell viability suppression, cell apoptosis promotion, tubule formation suppression, and cell migration suppression were partially abolished by CHRDL2 overexpression but amplified by CHRDL2 knockdown; consistent trends were observed in GCs-caused alterations in the protein levels of VEGFA, VEGFR2, and BMP-9 levels, and the ratios of Bax/Bcl-2 and cleaved-caspase3/Caspase3. GC stimulation significantly inhibited PI3K and Akt phosphorylation in BMECs, whereas the inhibitor effects of GCs on PI3K and Akt phosphorylation were partially attenuated by CHRDL2 overexpression but further amplified by CHRDL2 knockdown. Moreover, CHRDL2 overexpression caused improvement in GCs-induced damages to BMECs that were partially eliminated by PI3K inhibitor LY294002. In conclusion, CHRDL2 is down-regulated in NFH samples and GCs-stimulated BMECs. CHRDL2 overexpression could improve GCs-caused BMEC apoptosis and dysfunctions, possibly via the PI3K/Akt pathway.