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.

中文翻译：

---

在骨关节炎模型中，小的异二聚体伴侣相互作用亮氨酸拉链蛋白通过调节 AMPK/STAT3 信号通路抑制疼痛和软骨破坏


骨关节炎 （OA） 是一种由关节软骨和相邻骨骼分解引起的退行性关节疾病。关节损伤、超重、腿长差异、高水平的关节应力、异常的关节或肢体发育以及遗传因素与 OA 的病因有关。除了对关节的物理损伤外，炎症过程也已确定。小异二聚体伴侣相互作用亮氨酸拉链蛋白 （SMILE） 调节转录和许多细胞功能。在 SMILE 激活的蛋白质中，过氧化物酶体增殖物激活受体 （PPAR） γ介导 CD4 + T 辅助细胞（包括 Th1、Th2 和 Th17）以及 Treg 细胞的活性。PPAR-γ 与 STAT3 结合以抑制其转录，从而抑制 NF-κB 通路的表达，进而抑制炎性细胞因子干扰素 （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 C57BL/6 小鼠和 C57BL/6 衍生的 SMILE 过表达转基因 （SMILE Tg） 小鼠中诱导 OA。通过免疫组化和免疫荧光图像分析关节和脾组织中的蛋白表达水平。此外，进行流式细胞术检测免疫细胞变化的变化。在 SMILE Tg 小鼠中观察到较少的软骨损伤和 OA 生物标志物 （MMP13 、 TIMP3 和 MCP-1） 水平显著降低。为鉴定 SMILE 表达与 OA 之间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 IL-1β 、 IL-6 、 TNF-α 和磷酸化 AMPK 水平降低，软骨和滑膜中磷酸化 STAT3 水平显著降低。 通过流式细胞术研究全身免疫细胞的变化，以分析从对照和 SMILE Tg 小鼠中分离的脾细胞。SMILE Tg 小鼠 CD4 + IL-4 + 细胞 （Th2） 和 CD4 + CD25 + Foxp3 + 细胞 （Treg） 比例升高，CD4 + IL-17 + 细胞 （Th17） 比例显著降低。我们的结果表明，过表达的 SMILE 通过增加 AMPK 信号传导和降低 STAT3 来减轻 OA 的症状，从而降低炎症免疫细胞的水平。