Jiang Yuyun, Wang Shang, Zhu Wei, Liu Xi, Yang Yanwei, Huo Liyue, Ye Jixian, Ma Yongbin, Zhou Yuepeng, Yang Zhe, Mao Jiahui, Wang Xuefeng
Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People's Republic of China.
Tzu Chi International College of Traditional Chinese Medicine, Vancouver, BC, Canada.
Immunotargets Ther. 2025 Mar 24;14:259-278. doi: 10.2147/ITT.S512768. eCollection 2025.
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.
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.
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.
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.
骨关节炎（OA）是一种广泛存在的退行性关节疾病，主要影响老年人，可导致残疾。目前仍缺乏骨关节炎的生物标志物，因此无法及时进行干预。
使用LASSO和SVM-RFE从人类软骨数据集中鉴定骨关节炎生物标志物，随后进行ROC分析。由于LOXL1在骨关节炎软骨中高表达且具有强大的预测性能，因此被优先进行进一步研究。采用前交叉韧带横断（ACLT）手术诱导的骨关节炎大鼠，探讨LOXL1与炎症因子及巨噬细胞之间的相关性。从用LOXL1处理的巨噬细胞中，或在LOXL1 siRNA沉默后与软骨细胞共培养的巨噬细胞中检测巨噬细胞标志物和细胞因子分泌。
鉴定出五个具有骨关节炎特异性表达的关键生物标志物。患者中LOXL1升高与IL-6和IL-8相关，骨关节炎大鼠中M1巨噬细胞增加。LOXL1刺激的巨噬细胞上调CD86和炎性细胞因子。在软骨细胞中沉默LOXL1可降低共培养巨噬细胞中的CD86、炎性细胞因子以及NF-κB p65和p-STAT3表达，减轻MMP13和软骨细胞凋亡。STAT3和NF-κB信号抑制降低了LOXL1刺激的巨噬细胞中p-STAT3、p-p65、CD86、IL-6和IL-1β的表达。
本研究强调了LOXL1在通过NF-κB和STAT3信号激活M1巨噬细胞中的关键作用，从而促进促炎细胞因子分泌并促成骨关节炎发病机制。LOXL1有望作为骨关节炎炎症早期诊断的潜在标志物和新型治疗靶点。
