1. Academic Validation
  2. Nitisinone attenuates cartilage degeneration and subchondral osteoclastogenesis in osteoarthritis and concomitantly inhibits the cGAS/STING/NF-κB pathway

Nitisinone attenuates cartilage degeneration and subchondral osteoclastogenesis in osteoarthritis and concomitantly inhibits the cGAS/STING/NF-κB pathway

  • Eur J Pharmacol. 2024 Jan 12:176326. doi: 10.1016/j.ejphar.2024.176326.
Tao Yang 1 Haiwei Ma 1 Hehuan Lai 1 Yahong Lu 1 Kainan Ni 1 Xingyu Hu 1 Yang Zhou 1 Zhiguo Zhou 1 Weiqing Li 1 Jiawei Fang 1 Yejin Zhang 1 Zhenzhong Chen 2 Dengwei He 3
Affiliations

Affiliations

  • 1 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang, PR China, 323000.
  • 2 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang, PR China, 323000. Electronic address: 379095641@qq.com.
  • 3 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, 289 Kuocang Road, Lishui, Zhejiang, PR China, 323000. Electronic address: hedw_spine@163.com.
Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and subchondral bone remodelling. Currently, conservative treatment strategies cannot effectively alleviate the progression of OA. In this study, we used computer network analysis to show that Nitisinone (NTBC) is closely related to extracellular matrix degradation in OA and mainly interferes with the TNF-α signaling pathway. NTBC is an orphan drug used to treat hereditary type I tyrosinemia by altering phenylalanine/tyrosine metabolic flow. In this study, we found that NTBC effectively reduced chondrocyte inflammation and extracellular matrix degradation induced by TNF-α. Mechanistically, NTBC inhibited the cGAS/STING signaling pathway and reduced activation of the STING-dependent NF-κB pathway to alleviate inflammation. In addition, NTBC inhibited osteoclastogenesis and delayed the occurrence of subchondral bone remodelling. In mice with ACLT-induced osteoarthritis, intra-articular injection of NTBC significantly reduced cartilage degradation and subchondral bone remodelling. NTBC showed impressive therapeutic efficacy as a potential pharmaceutical intervention for the treatment of OA.

Keywords

Chondrocytes; Nitisinone; Osteoarthritis; Osteoclastogenesis; cGAS/STING/NF-κB pathway.

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