Lysyl Oxidase-Like 1 (LOXL1) Up-Regulation in Chondrocytes Promotes M1 Macrophage Activation in Osteoarthritis via NF-κB and STAT3 Signaling

Yuyun Jiang,1,* Shang Wang,2,* Wei Zhu,1,3 Xi Liu,1 Yanwei Yang,1 Liyue Huo,1 Jixian Ye,1 Yongbin Ma,1,4 Yuepeng Zhou,1 Zhe Yang,1 Jiahui Mao,1 Xuefeng Wang1,5 1Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China; 2Tzu Chi International College of Traditional Chinese Medicine, Vancouver, BC, Canada; 3Department of Sports Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China; 4Department of Central Laboratory, Jintan Hospital, Jiangsu University, Jintan, 213200, People’s Republic of China; 5Department of Nuclear Medicine, Institute of Digestive Diseases, and Institute of Endocrinology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuefeng Wang, Email [email protected]: Osteoarthritis (OA) constitutes a widespread degenerative joint disease predominantly affecting the elderly, leading to disability. There is still a lack of biomarkers for OA, so it cannot be intervened in time.Methods: OA biomarkers were identified from human cartilage datasets using LASSO and SVM-RFE, followed by ROC analysis. LOXL1 was prioritized for further research due to its high expression in OA cartilage and robust predictive performance. Anterior cruciate ligament transection (ACLT) surgery-induced OA rats were used to explore the correlation between LOXL1 and inflammatory factors and macrophages. Macrophage markers and cytokine secretion were detected from macrophages treated with LOXL1, or co-cultured with chondrocytes after LOXL1 siRNA silencing.Results: Five hub biomarkers with OA-specific expression were identified. Elevated LOXL1 correlated with IL-6 and IL-8 in patients and increased M1 macrophages in OA rats. LOXL1-stimulated macrophages upregulated CD86 and inflammatory cytokines. Silencing LOXL1 in chondrocytes reduced CD86, inflammatory cytokines, and NF-κB p65 and p-STAT3 expression in co-cultured macrophages, mitigating MMP13 and chondrocyte apoptosis. STAT3 and NF-κB signal inhibition reduces p-STAT3, p-p65, CD86, IL-6 and IL-1β expression in LOXL1-stimulated macrophages.Conclusion: This study underscores the pivotal role of LOXL1 in activating M1 macrophages through NF-κB and STAT3 signaling, thereby promoting pro-inflammatory cytokine secretion and contributing to OA pathogenesis. LOXL1 holds promise as a potential marker for early diagnosis of OA inflammation and as a novel therapeutic target.Keywords: lysyl oxidase-like 1, LOXL1, chondrocytes, macrophage activation, up-regulation, osteoarthritis