Atorvastatin Upregulates microRNA-186 and Inhibits the TLR4-Mediated MAPKs/NF-κB Pathway to Relieve Steroid-Induced Avascular Necrosis of the Femoral Head

Abstract

Steroid-induced avascular necrosis of the femoral head (SANFH) is caused by the death of active components of the femoral head owing to hormone overdoses. The use of lipid-lowering drugs to prevent SANFH in animals inspired us to identify the mechanisms involving Atorvastatin (Ato) in SANFH. However, it is still not well understood how and to what extent Ato affects SANFH. This study aimed to figure out the efficacy of Ato in SANFH and the underlying molecular mechanisms. After establishment of the SANFH model, histological evaluation, lipid metabolism, inflammatory cytokines, oxidative stress, apoptosis, and autophagy of the femoral head were evaluated. The differentially expressed microRNAs (miRs) after Ato treatment were screened out using microarray analysis. The downstream gene and pathway of miR-186 were predicted and their involvement in SANFH rats was analyzed. OB-6 cells were selected to simulate SANFH in vitro. Cell viability, cell damage, inflammation responses, apoptosis, and autophagy were assessed. Ato alleviated SANFH, inhibited apoptosis, and promoted autophagy. miR-186 was significantly upregulated after Ato treatment. miR-186 targeted TLR4 and inactivated the MAPKs/NF-κB pathway. Inhibition of miR-186 reversed the protection of Ato on SANFH rats, while inhibition of TLR4 restored the protective effect of Ato. Ato reduced apoptosis and promoted autophagy of OB-6 cells by upregulating miR-186 and inhibiting the TLR4/MAPKs/NF-κB pathway. In conclusion, Ato reduced apoptosis and promoted autophagy, thus alleviating SANFH via miR-186 and the TLR4-mediated MAPKs/NF-κB pathway.

Mechanism of vascular endothelial cell-derived exosomes modified with vascular endothelial growth factor in steroid-induced femoral head necrosis

“…SANFH is one of the most common hip pain diseases with an increasing incidence in recent years [1]. VEGF is an important angiogenic factor that regulates the proliferation, migration, and vascularization of VECs and plays a key role in bone formation and healing [3].…”

“…Steroid-induced avascular necrosis of the femoral head (SANFH) is common non-traumatic osteonecrosis, which is a progressive pathological process caused by high-dose and/or long-term use of dexamethasone (Dex) or other glucocorticoids (GC) [1]. The main characteristics of SANFH are femoral head degeneration, bone trabecula or bone marrow necrosis, extensive bone marrow edema, and adipocyte hyperplasia [2].…”

Novel anti-hyperuricemic hexapeptides derived fromApostichopus japonicushydrolysate and their modulation effects on the gut microbiota and host microRNA profile

“…32 Additionally, miR-186 showed inhibitory activity against the TLR4/NF-κB pathway in a mouse model. 33 In addition to regulating the related pathways, miR-488 and miR-920 were reported to directly target IL-1β. 34 All the related miRNAs except miR-488 and miR-920 were detected in this study, and the expected changing trend was found for miR-17-5p, which were downregulated in the model group and subsequently upregulated by the peptide treatments, while the expressions of miR-223 and miR-186 were only increased in the GPSGRP group compared to that of the model group (Table S9†).…”

“…19–21,45 Among the 49 differentially abundant genera identified in this study, genera Lactobacillus , Bifidobacterium and Enterococcus catalyze the hydrolysis of conjugated BAs to preserve the metabolic balance of BA, 46 genera Lactobacillus and Bifidobacterium converted tryptophan to indole and its derivatives, 47 and genera Lactobacillus , Akkermansia , Eubacterium and Blautia generated SCFAs by the degradation of dietary fiber. 33 Spearman's correlation analysis indicated that both Lactobacillus and Eubacterium correlated with four miRNAs, and genera related to the metabolism of SCFAs, tryptophan and BA were totally correlated with 17, 7 and 12 miRNAs (Table S10†), proposing the vital roles of microbiota metabolites between the gut microbiota and miRNAs.…”

O-linked β-N-acetylglucosaminylation may be a key regulatory factor in promoting osteogenic differentiation of bone marrow mesenchymal stromal cells

“…As the major source of osteoblasts, BMSCs are important contributors to the bone tissue repair process. The abnormal osteogenic differentiation of BMSCs is an important cause of bone metabolism-related diseases, including osteoporosis[ 2 , 3 ]. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is an important post-translational modification in which involves the attachment of a single O-linked N-acetylglucosamine (O-GlcNAc) moiety to Ser or Thr residues of cytoplasmic, nuclear, and mitochondrial proteins.…”