A sinomenine derivative alleviates bone destruction in collagen-induced arthritis mice by suppressing mitochondrial dysfunction and oxidative stress via the NRF2/HO-1/NQO1 signaling pathway

A sinomenine derivative alleviates bone destruction in collagen-induced arthritis mice by suppressing mitochondrial dysfunction and oxidative stress via the NRF2/HO-1/NQO1 signaling pathway

Bone destruction in rheumatoid arthritis (RA) leads to significant disability, yet effective treatments are limited. Sinomenine (Sino) demonstrates anti-arthritic and bone-protective effects but requires high doses. In this study, we developed a Sino derivative, SINX, and evaluated its efficacy in R...

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Main Authors: Wan-Yi Guo, Qi-Min Wu, Hao-Feng Zeng, Yu-Lian Chen, Jie Xu, Zhen-Yi Yu, Yong-Kang Shu, Xiao-Nan Yang, Chuan-Hai Zhang, Xi-Zi He, Jia-Ning Mi, Si Chen, Xiao-Man Chen, Jia-Qi Wu, He-Quan Yao, Liang Liu, Hu-Dan Pan
Format: Article
Language:English
Published: Elsevier 2025-05-01
Series:Pharmacological Research
Subjects:
Rheumatoid arthritis
Reactive oxygen species (ROS)
Mitochondrial function
Sinomenine derivatives
NRF2/HO-1/NQO1
Online Access:http://www.sciencedirect.com/science/article/pii/S1043661825001112
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Summary:Bone destruction in rheumatoid arthritis (RA) leads to significant disability, yet effective treatments are limited. Sinomenine (Sino) demonstrates anti-arthritic and bone-protective effects but requires high doses. In this study, we developed a Sino derivative, SINX, and evaluated its efficacy in RA. Safety assessments in mice confirmed its suitability for further study. In vitro, SINX inhibited osteoclast differentiation by reducing TRAP-positive cells, disrupting F-actin ring formation, and suppressing bone resorption pits, alongside downregulating osteoclast-specific genes. It also showed strong anti-inflammatory properties by reducing inflammatory cytokine levels. In vivo, using a collagen-induced arthritis (CIA) mouse model, SINX improved bone integrity by reducing joint inflammation, maintaining trabecular bone density, and preventing erosion. Histological and micro-CT analyses confirmed its effects, including suppressed osteoclast activity and reduced bone resorption-related gene expression. Mechanistically, SINX ameliorated mitochondrial dysfunction, decreased ROS levels, and activated the NRF2/HO-1/NQO1 pathway, enhancing antioxidant defenses. Compared to Sino, SINX achieved similar results at lower doses. These findings highlight the potential of SINX as a safe, effective treatment for RA-related bone destruction.
ISSN:1096-1186

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