Cortisol inhibits mTOR signaling in avascular necrosis of the femoral head.

BACKGROUND

ANFH is a major health problem, to which long lasting and definitive treatments are lacking. The aim of this study is to study RNA alterations attributed to cortisol-induced ANFH.

METHODS

Rat models were stratified into three groups: in vitro group (n = 20) for molecular biological assays, control group (n = 3), and ANFH group induced using lipopolysaccharide and dexamethasone (n = 3). Bone marrow-derived endothelial progenitor cells (BM-EPCs) were extracted from the rats. An RNA expression array was performed on BM-EPCs, and enriched genes were subject to pathway analysis. In vitro studies following findings of array results were also performed using the isolated BM-EPCs.

RESULTS

Significant alterations in mammalian target of rapamycin (mTOR) and HIF signaling pathways were identified in BM-EPCs of ANFH. By applying cortisol and dexamethasone to BM-EPCs, significant changes in mTOR and HIF elements were identified. The alteration of HIF pathways appeared to be downstream of mTOR signaling. Glucocorticoid receptor (GR) expression was related to glucocorticoid-dependent mRNA expression of mTOR/HIF genes. mTOR-dependent angiogenesis but not anabolism was the target of GR in ANFH. Inhibition of mTOR signaling also induced apoptosis of BM-EPCs via CHOP-dependent DR5 induction in response to GR stimulation.

CONCLUSION

Decreased mTOR signaling in response to GR stimulation leading to downregulated HIF pathway as well as increased apoptosis could be the pathophysiology.