Philpott Holly T, Birmingham Trevor B, Blackler Garth, Klapak J Daniel, Knights Alexander J, Farrell Easton C, Fiset Benoit, Walsh Logan A, Giffin J Robert, Vasarhelyi Edward M, MacDonald Steven J, Lanting Brent A, Maerz Tristan, Appleton C Thomas
University of Western Ontario and London Health Sciences Centre-University Hospital, London, Ontario, Canada.
University of Western Ontario, London, Ontario, Canada.
Arthritis Rheumatol. 2025 Jun;77(6):664-676. doi: 10.1002/art.43089. Epub 2025 Jan 26.
Uncontrolled pain remains a major clinical challenge in the management of knee osteoarthritis (OA), the most common disabling joint disease. Worse pain is associated with synovial innate immune cell infiltration (synovitis), but the role of innate immune-regulatory cells in pain is unknown. Our objective was to identify synovial innate immune cell subsets and pathophysiologic mechanisms associated with worse pain in patients with knee OA.
Synovial tissue biopsies from 122 patients with mild-to-severe knee OA pain (Knee Injury and OA Outcome Score [KOOS]) were analyzed to identify associations between synovial histopathology and worse pain. We then used spatial transcriptomics and proteomics of synovial tissue microenvironments (n = 32), followed by single-cell RNA sequencing (n = 8), to identify synovial cell composition and cell-cell communication networks in patients with more severe OA pain.
Histopathological signs of synovial microvascular dysfunction and perivascular edema were associated with worse KOOS pain (-10.76; 95% confidence interval [CI] -18.90 to -2.61). Patients with worse pain had fewer immune-regulatory macrophages, expanded fibroblast subsets, and enrichment in neurovascular remodeling pathways. Synovial macrophages from patients with worse pain expressed markers of immune exhaustion and decreased phagocytic function (-19.42%; 95% CI -35.96 to -2.89) and their conditioned media increased neuronal cell stress in dorsal root ganglia.
Although synovitis increases during OA, our findings suggest that exhaustion, dysfunction, and loss of immune-regulatory macrophages is associated with worse pain and may be an important therapeutic target.
在最常见的致残性关节疾病——膝骨关节炎（OA）的管理中，疼痛控制不佳仍然是一项重大的临床挑战。更严重的疼痛与滑膜固有免疫细胞浸润（滑膜炎）相关，但固有免疫调节细胞在疼痛中的作用尚不清楚。我们的目的是确定与膝骨关节炎患者更严重疼痛相关的滑膜固有免疫细胞亚群和病理生理机制。
对122例轻至重度膝骨关节炎疼痛患者（膝关节损伤和骨关节炎结局评分[KOOS]）的滑膜组织活检进行分析，以确定滑膜组织病理学与更严重疼痛之间的关联。然后，我们对滑膜组织微环境进行空间转录组学和蛋白质组学分析（n = 32），随后进行单细胞RNA测序（n = 8），以确定更严重骨关节炎疼痛患者的滑膜细胞组成和细胞间通信网络。
滑膜微血管功能障碍和血管周围水肿的组织病理学征象与更严重的KOOS疼痛相关（-10.76；95%置信区间[CI]-18.90至-2.61）。疼痛更严重的患者免疫调节性巨噬细胞较少，成纤维细胞亚群扩大，神经血管重塑途径富集。疼痛更严重患者的滑膜巨噬细胞表达免疫耗竭标志物，吞噬功能降低（-19.42%；95%CI -35.96至-2.89），其条件培养基增加背根神经节中的神经元细胞应激。
虽然骨关节炎期间滑膜炎会加重，但我们的研究结果表明，免疫调节性巨噬细胞的耗竭、功能障碍和丧失与更严重的疼痛相关，可能是一个重要的治疗靶点。
