Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050 Australia; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
CSL Ltd, Bio21 Institute, Parkville, Victoria 3050 Australia; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
Osteoarthritis Cartilage. 2023 Oct;31(10):1327-1341. doi: 10.1016/j.joca.2023.05.008. Epub 2023 May 22.
We have previously identified a granulocyte macrophage-colony stimulating factor (GM-CSF)/C-C motif ligand 17 (CCL17) pathway in monocytes/macrophages, in which GM-CSF regulates the formation of CCL17, and it is important for an experimental osteoarthritis (OA) model. We explore here additional OA models, including in the presence of obesity, such as a requirement for this pathway.
The roles of GM-CSF, CCL17, CCR4, and CCL22 in various experimental OA models, including those incorporating obesity (eight-week high-fat diet), were investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. Cell populations (flow cytometry) and cytokine messenger RNA (mRNA) expression (qPCR) in knee infrapatellar fat pad were analyzed. Human OA sera were collected for circulating CCL17 levels (ELISA) and OA knee synovial tissue for gene expression (qPCR).
We present evidence that: i) GM-CSF, CCL17, and CCR4, but not CCL22, are required for the development of pain-like behavior and optimal disease in three experimental OA models, as well as for exacerbated OA development due to obesity, ii) obesity alone leads to spontaneous knee joint damage in a GM-CSF- and CCL17-dependent manner, and iii) in knee OA patients, early indications are that BMI correlates with a lower Oxford Knee Score (r = -0.458 and p = 0.0096), with elevated circulating CCL17 levels (r = 0.2108 and p = 0.0153) and with elevated GM-CSF and CCL17 gene expression in OA synovial tissue.
The above findings indicate that GM-CSF, CCL17, and CCR4 are involved in obesity-associated OA development, broadening their potential as targets for possible treatments for OA.
我们之前在单核细胞/巨噬细胞中发现了粒细胞巨噬细胞集落刺激因子（GM-CSF）/C-C 基序配体 17（CCL17）通路，其中 GM-CSF 调节 CCL17 的形成，这对于实验性骨关节炎（OA）模型很重要。我们在这里探讨了其他 OA 模型，包括肥胖的存在，例如该通路的需求。
使用基因缺陷雄性小鼠研究 GM-CSF、CCL17、CCR4 和 CCL22 在各种实验性 OA 模型中的作用，包括合并肥胖的模型（八周高脂肪饮食）。通过相对静态体重分布和组织学分别评估疼痛样行为和关节炎。分析膝关节髌下脂肪垫的细胞群（流式细胞术）和细胞因子信使 RNA（qPCR）表达。收集人 OA 血清以检测循环 CCL17 水平（ELISA）和 OA 膝关节滑膜组织以检测基因表达（qPCR）。
我们提供的证据表明：i）GM-CSF、CCL17 和 CCR4，但不是 CCL22，对于三种实验性 OA 模型中疼痛样行为和最佳疾病的发展以及由于肥胖而导致的 OA 恶化的发展是必需的，ii）肥胖本身会导致 GM-CSF 和 CCL17 依赖性的自发膝关节损伤，iii）在膝骨关节炎患者中，早期迹象表明 BMI 与较低的牛津膝关节评分（r = -0.458，p = 0.0096）、循环 CCL17 水平升高（r = 0.2108，p = 0.0153）和 OA 滑膜组织中 GM-CSF 和 CCL17 基因表达升高相关。
上述发现表明 GM-CSF、CCL17 和 CCR4 参与了肥胖相关 OA 的发展，拓宽了它们作为 OA 潜在治疗靶点的潜力。
