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

Yusong Zhang,Limin Ma,Erhai Lu,Wenhua Huang

doi:10.3389/fphar.2021.583975

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.

Highlights

Steroid-induced avascular necrosis of the femoral head is a frequently occurring form of non-traumatic osteonecrosis and is a progressive pathological process caused by high dose and/or long-term use of dexamethasone (DEX) or other glucocorticoids (Lin et al, 2019; Cui et al, 2020)
hematoxylin and eosin (HE) staining was used to observe the injury of femoral heads in Steroid-induced avascular necrosis of the femoral head (SANFH) rats
Compared with the control rats, SANFH rats had higher serum TC and lowdensity lipoprotein to high-density lipoprotein (LDL/HDL), and lower serum OST content, while the TC and LDL/HDL of the SANFH rats treated with Ato were lower, and the OST content was higher (Figure 1B, all p < 0.01)

Summary

Introduction

Steroid-induced avascular necrosis of the femoral head is a frequently occurring form of non-traumatic osteonecrosis and is a progressive pathological process caused by high dose and/or long-term use of dexamethasone (DEX) or other glucocorticoids (Lin et al, 2019; Cui et al, 2020). The main features of SANFH are degeneration of the femoral head and necrosis of bone trabecula or bone marrow, widespread bone marrow oedema, and fat cell proliferation (Erken et al, 2012). By virtue of the development of molecular biology, a strong association of apoptosis with the pathogenesis of SANFH has been inferred (Cui et al, 2020). A comprehensive understanding of the apoptosis mechanisms of osteocytes will provide a novel insight to clarify the initiation and progression of SANFH, as well as to develop proper therapies to minimize or even eliminate the progression of it

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