Interferon β protects against avascular osteonecrosis through interleukin 6 inhibition and silent information regulator transcript-1 upregulation

Kyoung Min Kim,Sajeev Wagle,Kyu Yun Jang,Sung Il Wang,Young Jae Moon,Byung-Hyun Park,Jung Ryul Kim

doi:10.18632/oncotarget.23337

Kyoung Min Kim, Sajeev Wagle + Show 5 more

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https://doi.org/10.18632/oncotarget.23337

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Abstract

Synovitis of the affected joint is a common in avascular osteonecrosis (AVN). Increased levels of pro-inflammatory cytokine interleukin-6 (IL-6) have been reported in AVN, but the mechanism of this increase remains unclear. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, inhibits the release of inflammatory cytokines. Interferon β (IFN-β) has clear anti-inflammatory properties. We sought to investigate the effects of IFN-β treatment on AVN and to evaluate the specific signal pathway relating to IL-6 and SIRT1 affected during AVN. Using a dissection microscope, AVN was surgically induced in the distal femurs of mice. Exogenous IFN-β was administered to the model mice. The effects of exogenous IFN-β on AVN model mice were assessed using hematoxylin eosin and safranin-O staining, and bone resorption activity was measured using tartrate-resistant acid phosphatase (TRAP) and CD68 staining. Western blots, real-time RT-PCR, and immunohistochemical staining were performed to evaluate the production of SIRT1 and IL-6 in tissues. The RAW 264.7 cell line and bone marrow derived osteoclasts treated with exogenous IFN-β. Histological findings indicated well preserved trabecular bone and decreased osteoclast bone resorption activity in IFN-β treated mice compared with mice in the AVN group. Treatment with IFN-β increased SIRT1 expression and inhibited secretion of IL-6 in this AVN mouse model. IFN-β decreased IL-6 secretion by activating SIRT1 in the RAW 264.7 cell and bone marrow derived osteoclasts. Our work suggests that IFN-β could be used to treat AVN and that both SIRT1 and IL-6 are useful targets for treating patients with AVN.

Highlights

avascular osteonecrosis (AVN), known as osteonecrosis, or ischemic bone necrosis is a condition that causes bone destruction progressively as a result of compromised blood vessels of the bone, death of bone tissue and bone marrow cells [1,2,3]
We demonstrated that Interferon β (IFN-β) protects against AVN in a mice model by suppressing the secretion of the proinflammatory cytokine IL-6
We have shown that the effect of IFN-β on the suppression of IL-6 is mediated by its role in stimulating Silent information regulator transcript-1 (SIRT1) expression (Figure 9)

Summary

Introduction

AVN, known as osteonecrosis, or ischemic bone necrosis is a condition that causes bone destruction progressively as a result of compromised blood vessels of the bone, death of bone tissue and bone marrow cells [1,2,3]. Synovial inflammation in patients with AVN is common, the mechanism of the inflammation remains unclear [9]. According to a previous study, AVN patients have inflamed synovial tissues without having an inflammatory disease [10]. Recent genetic study found significantly overrepresented heterozygous subjects with an IL-6 polymorphism in a control group compared to the Legg-Calvé-Perthes disease (childhood form of ischemic osteonecrosis) group [11]. Another study reported that the protein level of the major proinflammatory cytokine IL-6 in synovial fluid was significantly elevated in Legg-Calvé-Perthes disease [12]. SIRT1 inhibits NF-kB transactivational activity by deacetylation. SIRT1 deacetylates Lys310 of the RelA/ p65 subunits of NF-kB and inhibits both its transcriptional activity and the release of inflammatory cytokines mediated by NF-kB [16].

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