Department of Orthopedic, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian, China; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
Biochem Pharmacol. 2024 Sep;227:116420. doi: 10.1016/j.bcp.2024.116420. Epub 2024 Jul 10.
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.
骨关节炎（OA）以慢性疼痛为特征，严重影响患者的生活质量。OA 发病机制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）作为 STAT 蛋白家族的一员，在介导炎症中发挥着关键作用。STX-0119 已被验证为一种能够特异性抑制 STAT3 的小分子化合物。然而，STX-0119 治疗 OA 的疗效仍有待评估。因此，本研究旨在探讨 STX-0119 治疗 OA 的疗效及其分子机制。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，向 OA 小鼠关节内注射 STX-0119 可减轻软骨退变，而不影响软骨下骨。此外，STX-0119 可抑制软骨中 STAT3 的磷酸化。在体外，STX-0119 可抑制白细胞介素-1β诱导的软骨细胞炎症模型中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实验的结果表明，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，在人软骨样本的离体培养中，STX-0119 通过 STAT3/PPARγ 信号通路被再次证实可抑制软骨退变。综上所述，我们的研究结果支持 STX-0119 作为一种抑制 STAT3 的治疗剂，用于治疗 OA 的潜力。
