Skatole Alleviates Osteoarthritis by Reprogramming Macrophage Polarization and Protecting Chondrocytes
Weiyun Wang,
Yaru Chu,
Yunkun Lu,
Jie Xu,
Weixuan Zhao,
Zhuo Liang,
Xueqiang Guo,
Lingling Xi,
Tao Han,
Yaping Shen,
Wenjuan Song,
Yanhua Tang,
Mengnan Wen,
Zhuang Qian,
Lei Wang,
Zhenlin Fan,
Guangdong Zhou,
Wenjie Ren
Affiliations
Weiyun Wang
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Yaru Chu
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Yunkun Lu
Department of General Surgery, Sir Run Run Shaw Hospital,
Zhejiang University School of Medicine, Hangzhou 310013, China.
Jie Xu
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Weixuan Zhao
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Zhuo Liang
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Xueqiang Guo
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Lingling Xi
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Tao Han
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Yaping Shen
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Wenjuan Song
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Yanhua Tang
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Mengnan Wen
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Zhuang Qian
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Lei Wang
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Zhenlin Fan
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Guangdong Zhou
Shanghai Key Lab of Tissue Engineering, Shanghai 9th People’s Hospital,
Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Wenjie Ren
Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration,
Xinxiang Medical University, Xinxiang 453003, China.
Osteoarthritis (OA) is the most prevalent joint disease, yet effective disease-modifying OA drugs (DMOADs) remain elusive. Targeting macrophage polarization has emerged as a promising avenue for OA treatment. This study identified skatole through high-throughput screening as an efficient modulator of macrophage polarization. In vivo experiments demonstrated that skatole administration markedly reduced synovitis and cartilage damage in both destabilization of medial meniscus (DMM)-induced OA mice and monosodium iodoacetate (MIA)-induced OA rats. Mechanistically, skatole activated signal transducer and activator of transcription 6 (Stat6) signaling, promoting M2 macrophage polarization, while inhibiting nuclear factor-κB (NFκB) and mitogen-activated protein kinase (MAPK) signaling pathways to suppress M1 polarization. RNA-sequencing analysis, targeted metabolomics, and mitochondrial stress tests further revealed that skatole treatment shifted macrophages toward oxidative phosphorylation for energy production. Additionally, it up-regulated genes associated with glutathione metabolism and reactive oxygen species (ROS) pathways, reducing intracellular ROS production. The CUT&Tag assay results indicated that the downstream transcription factor p65 of NFκB can directly bind to gene loci related to inflammation, oxidative phosphorylation, and glutathione metabolism, thereby modulating gene expression. This regulatory process is inhibited by skatole. At the chondrocyte level, conditional medium from skatole-treated M1 macrophages balanced anabolism and catabolism in mouse chondrocytes and inhibited apoptosis. In IL1β-treated chondrocytes, skatole suppressed inflammation and catabolism without affecting apoptosis or anabolism. Overall, skatole maintains immune microenvironment homeostasis by modulating macrophage polarization in joints and preserves cartilage function by balancing chondrocyte anabolism and catabolism, effectively alleviating OA. These findings suggest skatole’s potential as a DMOAD.
