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Selective STAT3 inhibitor STX-0119 alleviates osteoarthritis progression by modulating the STAT3/PPARγ signaling pathway.
Lu, Xuanyuan; Xu, Yangjun; Li, Xinhuo; Wang, Jing; Wang, Lei; Hu, Xujun; Fan, Honghui; Pang, Fei; Li, Xin; Pan, Xiaoyu; He, Wei; Li, Jianlei; Dai, Zhangsheng.
Afiliación
  • Lu X; 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.
  • Xu Y; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Li X; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Wang J; Department of Pediatric, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Wang L; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Hu X; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Fan H; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Pang F; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Li X; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Pan X; Department of Orthopedic, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian, China.
  • He W; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Li J; Department of Orthopedic, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang, China.
  • Dai Z; Department of Orthopedic, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian, China. Electronic address: daizhangsheng56@fjmu.edu.cn.
Biochem Pharmacol ; 227: 116420, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38996934
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-1ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoartritis / Transducción de Señal / PPAR gamma / Factor de Transcripción STAT3 / Ratones Endogámicos C57BL Límite: Animals / Humans / Male Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoartritis / Transducción de Señal / PPAR gamma / Factor de Transcripción STAT3 / Ratones Endogámicos C57BL Límite: Animals / Humans / Male Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido