Abstract：
Osteoarthritis (OA), characterized by chronic pain, significantly affects the quality of life of affected individuals. Key factors in OA pathogenesis include cartilage degradation and inflammation. Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, plays a pivotal role in mediating inflammation. STX-0119 has been verified as a small molecular compound that can specifically inhibit STAT3. However, the efficacy of STX-0119 in the treatment of OA remains to be evaluated. Therefore, the aim of this study was to explore the therapeutic effects and molecular mechanisms of STX-0119 in the treatment of OA. We found that the expression of phosphorylated STAT3 is upregulated in human OA cartilage as well as in the cartilage of a mouse model of OA. In vivo, joint injection of STX-0119 into OA mice alleviated cartilage degeneration without affecting the subchondral bone. Additionally, STX-0119 could inhibit the phosphorylation of STAT3 in the cartilage. In vitro, STX-0119 suppressed inflammatory responses in chondrocytes and promoted anabolic metabolism in an interleukin-1β-induced chondrocyte inflammation model. Additionally, the results of transcriptome sequencing and lentiviral infection assays demonstrated that in chondrocytes, STX-0119 induces the upregulation of peroxisome proliferators-activated receptor gamma (PPARγ) expression by inhibiting STAT3 phosphorylation. Finally, in ex vivo cultures of human cartilage samples, STX-0119 was reaffirmed to inhibit cartilage degeneration via the STAT3/PPARγ signaling pathway. Together, our findings support the potential of STX-0119 for development as a therapeutic agent targeting STAT3 for the treatment of OA.
摘要：
骨关节炎(OA),以慢性疼痛为特征，显著影响受影响个体的生活质量。OA发病的关键因素包括软骨降解和炎症。信号转导和转录激活因子3（STAT3），STAT蛋白家族的一员,在介导炎症中起关键作用。STX-0119已被证实为可以特异性抑制STAT3的小分子化合物。然而,STX-0119治疗OA的疗效尚待评估.因此,本研究旨在探讨STX-0119治疗OA的疗效及分子机制。我们发现磷酸化STAT3的表达在人OA软骨以及OA小鼠模型的软骨中上调。在体内,STX-0119联合注射到OA小鼠中减轻软骨退变而不影响软骨下骨。此外,STX-0119可抑制软骨中STAT3的磷酸化。体外，STX-0119在白细胞介素-1β诱导的软骨细胞炎症模型中抑制软骨细胞的炎症反应并促进合成代谢。此外,转录组测序和慢病毒感染测定的结果表明，在软骨细胞中，STX-0119通过抑制STAT3磷酸化诱导过氧化物酶体增殖物激活受体γ(PPARγ)表达上调。最后,在人软骨样品的离体培养中，重申STX-0119通过STAT3/PPARγ信号通路抑制软骨退变。一起,我们的研究结果支持STX-0119作为靶向STAT3治疗OA的治疗药物的开发潜力.
