Abstract
BackgroundANFH 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.MethodsRat 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.ResultsSignificant 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.ConclusionDecreased mTOR signaling in response to GR stimulation leading to downregulated HIF pathway as well as increased apoptosis could be the pathophysiology.
Highlights
Avascular necrosis of the femoral head (ANFH) is a major health problem, to which long lasting and definitive treatments are lacking
The mammalian target of rapamycin pathway was significantly downregulated in DEX-treated rats (P = 0.04996)
Given the knowledge-based angiogenesis regulatory pathway putting mammalian target of rapamycin (mTOR) upstream of HIF-1 signaling, it was hypothesized that initial mTOR inhibition by glucocorticoids in ANFH exerted anti-angiogenic effect via HIF-1 signaling
Summary
ANFH is a major health problem, to which long lasting and definitive treatments are lacking. Avascular necrosis of the femoral head (ANFH) is a major health problem [1]. The pathological process initiates at the loading region of the femoral head. Treatment other than surgery for ANFH is inconclusive, mainly due to uncertainty of its etiology aside from trauma, the one associated with inherent alteration of bone tissue, most commonly caused by chronic alcohol intoxication or excessive steroid use [5]. ANFH caused by steroid is even more detrimental as the population is often diagnosed at a younger age. This is often a result of pharmacologic doses of steroids used to treat inflammatory or autoimmune disorders. There has been a dearth of evidence that steroid could directly inhibit angiogenic potential of the femoral head
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