Osteoarthritis (OA), the most prevalent form of arthritis disease, is characterized by destruction of articular cartilage, osteophyte development, and sclerosis of subchondral bone. Transcription factors Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and Forkhead box M1 (FOXM1) are key mediators of this inflammatory reaction. In this study, we investigated the interaction between JAK1/STAT3 and FOXM1 in OA. Inflammation is related to the cartilage damage, and lipopolysaccharides (LPS) are a major pro-inflammatory inducer, so LPS was utilized to stimulate chondrocytes and establish a cell-based OA model. We found LPS treatment caused a generation of inflammatory cell factors (IL-1β, IL-6, and TNF-α), and upregulation of inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), prostaglandin E2 (PGE2) and other inflammatory mediators. Cell viability of chondrocytes was impaired with LPS stimulation, along with an upregulation of JAK1 expression, and phosphorylation and nuclear accumulation of STAT3. The administration of STAT3 inhibitor WP1066, which abated activation and nuclear location of STAT3, depleted the effect of LPS on inflammation and cell death. Co-immunoprecipitation showed that STAT3 was able to bind to FOXM1, and deactivation of STAT3 resulted in the downregulation of FOXM1. Moreover, FOXM1 silencing inhibited the generation of inflammatory cytokines induced by LPS, and the attenuation of cell survival. These findings indicated that the interaction between JAK1/STAT3 and FOXM1 may play a key role in OA pathogenic studies, and suggest the JAK1/STAT3 pathway may be a potential target for OA therapy.

骨关节炎 (OA) 是最普遍的关节炎疾病形式，其特征在于关节软骨的破坏、骨赘的发育和软骨下骨的硬化。转录因子 Janus 激酶 1/信号转导和转录激活因子 3 (JAK1/STAT3) 和 Forkhead box M1 (FOXM1) 是这种炎症反应的关键介质。在这项研究中，我们研究了 OA 中 JAK1/STAT3 和 FOXM1 之间的相互作用。炎症与软骨损伤有关，脂多糖（LPS）是主要的促炎诱导物，因此利用LPS刺激软骨细胞并建立基于细胞的OA模型。我们发现 LPS 治疗引起炎症细胞因子（IL-1β、IL-6 和 TNF-α）的产生，以及诱导型一氧化氮合酶 (iNOS)、环氧合酶-2 (COX-2)、一氧化氮 (NO ), 前列腺素 E2 (PGE2) 和其他炎症介质。软骨细胞的细胞活力因 LPS 刺激而受损，同时 JAK1 表达上调，以及 STAT3 的磷酸化和核积累。STAT3 抑制剂 WP1066 的施用减弱了 STAT3 的活化和核定位，从而消除了 LPS 对炎症和细胞死亡的影响。共免疫沉淀表明 STAT3 能够与 FOXM1 结合，而 STAT3 的失活导致 FOXM1 的下调。此外，FOXM1 沉默抑制了 LPS 诱导的炎性细胞因子的产生，并降低了细胞存活率。这些发现表明 JAK1/STAT3 和 FOXM1 之间的相互作用可能在 OA 致病性研究中发挥关键作用，并提示 JAK1/STAT3 通路可能是 OA 治疗的潜在靶点。