PDF(Pubmed)
Abstract：
Rheumatoid arthritis is a chronic inflammatory disease that shows characteristic diurnal variation in symptom severity, where joint resident fibroblast-like synoviocytes (FLS) act as important mediators of arthritis pathology. We investigate the role of FLS circadian clock function in directing rhythmic joint inflammation in a murine model of inflammatory arthritis. We demonstrate FLS time-of-day-dependent gene expression is attenuated in arthritic joints, except for a subset of disease-modifying genes. The deletion of essential clock gene Bmal1 in FLS reduced susceptibility to collagen-induced arthritis but did not impact symptomatic severity in affected mice. Notably, FLS Bmal1 deletion resulted in loss of diurnal expression of disease-modulating genes across the joint, and elevated production of MMP3, a prognostic marker of joint damage in inflammatory arthritis. This work identifies the FLS circadian clock as an influential driver of daily oscillations in joint inflammation, and a potential regulator of destructive pathology in chronic inflammatory arthritis.
摘要：
类风湿性关节炎是一种慢性炎症性疾病，表现出症状严重程度的特征性昼夜变化，其中关节驻留成纤维细胞样滑膜细胞（FLS）作为关节炎病理的重要介质。我们研究了FLS昼夜节律时钟功能在指导炎症性关节炎小鼠模型中的节律性关节炎症中的作用。我们证明FLS的一天时间依赖性基因表达在关节炎关节中减弱，除了一部分疾病修饰基因.FLS中必需时钟基因Bmal1的缺失降低了对胶原诱导的关节炎的易感性，但不影响受影响小鼠的症状严重程度。值得注意的是,FLSBmal1缺失导致疾病调节基因在关节中的昼夜表达丧失，以及炎性关节炎中关节损伤的预后标志物MMP3的产生升高。这项工作将FLS昼夜节律时钟确定为关节炎症日常振荡的有影响力的驱动因素，和慢性炎症性关节炎的破坏性病理的潜在调节剂。
