Zeng Runming, Lu Xiaohui, Lin Jing, Ron Zhijie, Fang Jiezhuang, Liu Zewa, Zeng Wanting
Department of Orthopedic Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China.
Department of Oncology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China.
Exp Biol Med (Maywood). 2021 Mar;246(6):644-653. doi: 10.1177/1535370220974933. Epub 2020 Dec 9.
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）是最常见的关节炎疾病形式，其特征在于关节软骨破坏、骨赘形成和软骨下骨硬化。转录因子Janus激酶1/信号转导和转录激活因子3（JAK1/STAT3）和叉头框M1（FOXM1）是这种炎症反应的关键介质。在本研究中，我们研究了OA中JAK1/STAT3与FOXM1之间的相互作用。炎症与软骨损伤有关，脂多糖（LPS）是主要的促炎诱导剂，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处理导致炎症细胞因子（IL-1β、IL-6和TNF-α）的产生，以及诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）、一氧化氮（NO）、前列腺素E2（PGE2）和其他炎症介质的上调。LPS刺激会损害软骨细胞的活力，同时JAK1表达上调，STAT3磷酸化并在细胞核中积累。给予STAT3抑制剂WP1066可减少STAT3的激活和核定位，消除LPS对炎症和细胞死亡的影响。免疫共沉淀显示STAT3能够与FOXM1结合，STAT3失活导致FOXM1下调。此外，FOXM1沉默抑制了LPS诱导的炎症细胞因子的产生以及细胞存活能力的减弱。这些发现表明JAK1/STAT3与FOXM1之间的相互作用可能在OA致病机制研究中起关键作用，并提示JAK1/STAT3通路可能是OA治疗的潜在靶点。
