Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway

IF 4.9 2区医学 Q1 Medicine

Arthritis Research & Therapy Pub Date : 2024-11-12 DOI:10.1186/s13075-024-03417-3

Jeonghyeon Moon, Keun-Hyung Cho, JooYeon Jhun, JeongWon Choi, Hyun-Sik Na, Jeong Su Lee, Seung Yoon Lee, Jun-Ki Min, Anan Shetty, Sung-Hwan Park, Seok Jung Kim, Mi-La Cho

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引用次数: 0

Abstract

Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB. OA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells. Less cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17). Our results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells.

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通过调节 AMPK/STAT3 信号通路抑制骨关节炎模型中的疼痛和软骨损伤

骨关节炎（OA）是一种退行性关节疾病，由关节软骨和邻近骨质破坏引起。关节损伤、超重、腿长短不一、关节压力过大、关节或肢体发育异常以及遗传因素都与 OA 的病因有关。除了关节的物理损伤外，炎症过程的作用也已被确认。小异质二聚体相互作用亮氨酸拉链蛋白（SMILE）调节转录和许多细胞功能。SMILE 激活的蛋白质包括过氧化物酶体增殖激活受体（PPAR）γ，它介导 CD4 + T 辅助细胞（包括 Th1、Th2 和 Th17）以及 Treg 细胞的活动。PPAR-γ 与 STAT3 结合以抑制其转录，从而抑制 NF-κB 通路的表达，进而抑制炎症细胞因子干扰素 (IFN)、白细胞介素 (IL)-1β、IL-6 和肿瘤坏死因子 (TNF)-α 的表达，它们是 STAT3 和 NF-κB 的子信号。在对照组C57BL/6小鼠和C57BL/6衍生的SMILE高表达转基因（SMILE Tg）小鼠中诱导OA。通过免疫组化和免疫荧光图像分析了关节和脾脏组织中的蛋白表达水平。此外，还采用流式细胞术检测免疫细胞的变化。在SMILE Tg小鼠中观察到的软骨损伤较少，OA生物标志物（MMP13、TIMP3和MCP-1）水平明显降低。为确定SMILE表达与OA之间的联系所涉及的信号通路而进行的免疫组化显示，滑膜组织中的IL-1β、IL-6、TNF-α和磷酸化AMPK水平下降，软骨和滑膜中的磷酸化STAT3水平也显著下降。通过流式细胞术分析从对照组和 SMILE Tg 小鼠体内分离出来的脾细胞，研究了全身免疫细胞的变化。SMILE Tg 小鼠的 CD4 + IL-4 + 细胞（Th2）和 CD4 + CD25 + Foxp3 + 细胞（Treg）比例升高，而 CD4 + IL-17 + 细胞（Th17）明显减少。我们的研究结果表明，过表达的SMILE通过增加AMPK信号传导和减少STAT3，从而降低炎性免疫细胞的水平，减轻了OA的症状。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis Research & Therapy RHEUMATOLOGY-

CiteScore

8.60

自引率

2.00%

发文量

261

审稿时长

14 weeks

期刊介绍： Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.