1. Academic Validation
  2. Targeted inhibition of STAT3 (Tyr705) by xanthatin alleviates osteoarthritis progression through the NF-κB signaling pathway

Targeted inhibition of STAT3 (Tyr705) by xanthatin alleviates osteoarthritis progression through the NF-κB signaling pathway

  • Biomed Pharmacother. 2024 Mar 22:174:116451. doi: 10.1016/j.biopha.2024.116451.
Yangjun Xu 1 Zhuolin Chen 2 Xuanyuan Lu 2 Jiewen Zheng 1 Xuewen Liu 2 Tan Zhang 2 Wanlei Yang 3 Yu Qian 4
Affiliations

Affiliations

  • 1 School of Medicine, Shaoxing University, Shaoxing, Zhejiang 312000, China.
  • 2 Department of Orthopedics, Shaoxing People's Hospital (Shaoxing hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang 312000, China.
  • 3 Department of Orthopedics Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, China. Electronic address: 20223010@zcmu.edu.cn.
  • 4 Department of Orthopedics Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, China. Electronic address: 20223022@zcmu.edu.cn.
Abstract

The transcription factor, signal transducer, and stimulator of transcription 3 (STAT3) is a potential target in osteoarthritis (OA) treatment. Although xanthatin (XA), a biologically active substance derived from Xanthium strumarium L, specifically inhibits STAT3 phosphorylation at Tyr705, the mechanism underlying its inhibitory effect on OA progression remains unclear. In this study, our objective was to explore the therapeutic effects exerted by XA on OA and the underlying molecular mechanisms. The effects of XA treatment on mouse OA models subjected to destabilization of the medial meniscus using medial collateral ligament transection, as well as on interleukin-1β (IL-1β)-induced mouse chondrocytes, were examined. Histological changes in cartilage and subchondral bone (SCB), as well as changes in the expression levels of osteophytes, cartilage degeneration- and osteoclast differentiation-related factors, and the role of XA-related signaling pathways in human cartilage tissue, were studied using different techniques. XA inhibited STAT3 phosphorylation at Tyr705 and further attenuated the activity of nuclear factor-κB (NF-κB) in chondrocytes and osteoclasts. In vitro, XA administration alleviated pro-inflammatory cytokine release, extracellular matrix catabolism, and RANKL-mediated osteoclast differentiation. In vivo, intraperitoneal injection of XA exerted a protective effect on cartilage degeneration and SCB loss. Similarly, XA exerted a protective effect on human cartilage tissue by inhibiting the STAT3/NF-κB signaling pathway. Overall, our study elucidated the therapeutic potential of XA as a small-molecule inhibitor of STAT3-driven OA progression. This discovery may help enhance innovative clinical interventions against OA.

Keywords

STAT3 Tyr705; chondrocytes; osteoarthritis; osteoclasts; xanthatin.

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