Department of Orthopaedic, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, PR China.
Department of Orthopaedic, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, PR China.
Tissue Cell. 2022 Oct;78:101906. doi: 10.1016/j.tice.2022.101906. Epub 2022 Aug 24.
BACKGROUND/AIM: Osteoarthritis (OA) is a common total joint disorder associated with regulatory T cell (Treg)/IL-17-producing T helper (Th17) cell imbalance. This study elucidated the mechanism underlying Th17/Treg imbalance during OA progression.
CD4 T cells were isolated and induced to differentiate and obtain Th17 and Treg cells, and an OA mouse model was established by anterior cruciate ligament transection surgery, followed by loss- and gain-of-function assays. Max interacting protein 1 (MXI1), tectonic family member 2 (TCTN2), Forkhead Box Protein P3 (Foxp3), signal transducer and activator of transcription 3 (STAT3), and retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) expression was determined in cells and mice, accompanied by the measurement of the proportion of Th17 and Treg cells and the levels of interleukin (IL)- 1β, tumor necrosis factor (TNF)-α, and interferon (INF)-γ. Articular cartilage histopathology was observed by hematoxylin and eosin staining and Safranin O-Fast Green staining. Relationship between MXI1 and TCTN2 was assessed.
Bioinformatics analysis identified MXI1 and TCTN2 upregulation in OA patients. Mechanistically, MXI1 bound to TCTN2 promoter to promote its transcription. Upregulated MXI1 boosted INF-γ, STAT3, IL-1β, TNF-α, and RORγt levels and Th17 cell differentiation, but restricted Foxp3 expression and Treg cell differentiation in CD4 T cells. Effects caused by overexpressed MXI1 were negated by silenced TCTN2. Also, the impacts of MXI1 overexpression on Th17/Treg imbalance and IL-1β, STAT3, TNF-α, Foxp3, INF-γ, and RORγt expression were further validated in OA mice, accompanied by aggravated articular cartilage degeneration.
Conclusively, MXI1 facilitated Th17/Treg imbalance to accelerate OA progression.
背景/目的：骨关节炎（OA）是一种常见的全关节疾病，与调节性 T 细胞（Treg）/IL-17 产生的辅助性 T 细胞（Th17）失衡有关。本研究阐明了 OA 进展过程中 Th17/Treg 失衡的机制。
分离 CD4 T 细胞并诱导其分化以获得 Th17 和 Treg 细胞，通过前交叉韧带切断术建立 OA 小鼠模型，然后进行失活和功能获得实验。在细胞和小鼠中测定最大相互作用蛋白 1（MXI1）、构造家族成员 2（TCTN2）、叉头框蛋白 P3（Foxp3）、信号转导和转录激活因子 3（STAT3）和维甲酸受体相关孤儿核受体γ t（RORγt）的表达，并测定 Th17 和 Treg 细胞的比例以及白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α 和干扰素（INF）-γ 的水平。通过苏木精和伊红染色和番红 O-快绿染色观察关节软骨组织病理学。评估 MXI1 和 TCTN2 之间的关系。
生物信息学分析发现 OA 患者 MXI1 和 TCTN2 上调。在机制上，MXI1 结合到 TCTN2 启动子上以促进其转录。上调的 MXI1 增加了 INF-γ、STAT3、IL-1β、TNF-α 和 RORγt 水平并促进 Th17 细胞分化，但在 CD4 T 细胞中限制 Foxp3 表达和 Treg 细胞分化。沉默 TCTN2 可消除过表达 MXI1 引起的作用。此外，在 OA 小鼠中进一步验证了 MXI1 过表达对 Th17/Treg 失衡以及 IL-1β、STAT3、TNF-α、Foxp3、INF-γ 和 RORγt 表达的影响，同时伴有关节软骨退化加重。
总之，MXI1 促进 Th17/Treg 失衡加速 OA 进展。
