Carpaine alleviates tendinopathy in mice by promoting the ubiquitin-proteasomal degradation of p65 via targeting the E3 ubiquitin ligase LRSAM1

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Xuemei Lin - , Guangzhou Medical University (Author)
  • Xinggui Tian - , University Center for Orthopedics, Trauma and Plastic Surgery (Author)
  • Huaji Jiang - , Southern Medical University (Author)
  • Wenjun Li - , Guangdong Second Provincial General Hospital (Author)
  • Chaomin Wang - , Southern Medical University (Author)
  • Jianping Wu - , Guangzhou Medical University (Author)
  • Weidong Chen - , Guangzhou Medical University (Author)
  • Weizhe Shi - , Guangzhou Medical University (Author)
  • Qinyu Tian - , TUD Dresden University of Technology (Author)
  • Xiaoqian Gong - , Southern Medical University (Author)
  • Qinghe Zhou - , Guangzhou Medical University (Author)
  • Hongwen Xu - , Guangzhou Medical University (Author)
  • Stefan Zwingenberger - , University Center for Orthopedics, Trauma and Plastic Surgery (Author)

Abstract

BACKGROUND: Currently, there are no specific drugs or targets available for the treatment of tendinopathy. However, inflammation has recently been found to play a pivotal role in tendinopathy progression, thereby identifying it as a potential therapeutic target. Carpaine (CA) exhibits potential anti-inflammatory pharmacological properties and may offer a therapeutic option for tendinopathy.

PURPOSE: This study aimed to investigate the effectiveness of CA in addressing tendinopathy and uncovering its underlying mechanisms.

METHODS: Herein, the efficacy of CA by local administration in vivo in comparison to the first-line drug indomethacin was evaluated in a mouse collagenase-induced tendinopathy (CIT) model. Furthermore, IL-1β induced a simulated pathological inflammatory microenvironment in tenocytes to investigate its underlying mechanisms in vitro. Further confirmation experiments were performed by overexpressing or knocking down the selective targets of CA in vivo.

RESULTS: The findings demonstrated that CA was dose-dependent in treating tendinopathy and that the high-dose group outperformed the first-line drug indomethacin. Mechanistically, CA selectively bound to and enhanced the activity of the E3 ubiquitin ligase LRSAM1 in tendinopathy. This effect mediated the ubiquitination of p65 at lysine 93, subsequently promoting its proteasomal degradation. As a result, the NF-κB pathway was inactivated, leading to a reduction in inflammation of tendinopathy. Consequently, CA effectively mitigated the progression of tendinopathy. Moreover, the LRSAM1 overexpression demonstrated effectiveness in mitigating the tendinopathy progression and its knockdown abolished the therapeutic effects of CA.

CONCLUSION: CA attenuates the progression of tendinopathy by promoting the ubiquitin-proteasomal degradation of p65 via increasing the enzyme activity of LRSAM1. The exploration of LRSAM1 has also unveiled a new potential target for treating tendinopathy based on the ubiquitin-proteasomal pathway.

Details

Original languageEnglish
Article number155323
Number of pages14
JournalPhytomedicine
Volume124
Early online date27 Dec 2023
Publication statusPublished - Feb 2024
Peer-reviewedYes

External IDs

Scopus 85182441196

Keywords

Keywords

  • Alkaloids, Animals, Ubiquitin-Protein Ligases/metabolism, Tendinopathy/drug therapy, Inflammation/metabolism, Ubiquitin/metabolism, Mice, Indomethacin

Library keywords