Department of Physiology & Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Health & Rehabilitation Sciences, Faculty of Health Sciences, Western University, London, ON, Canada.
Front Immunol. 2022 May 24;13:890094. doi: 10.3389/fimmu.2022.890094. eCollection 2022.
Synovial inflammation in knee osteoarthritis (OA) causes disorganized synovial angiogenesis and complement activation in synovial fluid, but links between complement and synovial microvascular pathology have not been established. Since complement causes vascular pathology in other diseases and since sex-differences exist in complement activation and in OA, we investigated sex differences in synovial fluid complement factors, synovial tissue vascular pathology, and associations between complement and synovial vascular pathology in patients with late-stage knee OA.
Patients with symptomatic, late-stage radiographic knee OA undergoing total knee arthroplasty or high tibial osteotomy provided matched synovial fluid and tissue biopsies during surgery. Complement factors (C2, C5, adipsin, MBL, and CFI) and terminal complement complex (sC5b-C9) were measured in synovial fluid by multiplex or enzyme-linked immunosorbent assay, respectively. Features of synovial vascular pathology (vascularization, perivascular edema, and vasculopathy) were assessed by histopathology. Multivariate linear regression models were used to assess associations between synovial fluid complement factors and histopathological features of vascular pathology, with adjustment for age, sex, body mass index, and sex interaction. Sex-disaggregated comparisons were completed.
Synovial fluid biomarker and histopathology data were included from 97 patients. Most synovial fluid complement factors and synovial tissue histopathological features were similar between sexes. Synovial fluid C5 trended to lower levels in males (-20.93 ng/mL [95%CI -42.08, 0.23] 0.05). Median vasculopathy scores (0.42 [95%CI 0.07, 0.77] 0.02) were higher in males. In the full cohort, C5 concentration was associated with lower vascularization scores (-0.005 [95%CI -0.010, -0.0001] 0.04) while accounting for sex*C5 interaction. In sex-disaggregated analyses, increased C5 concentration was associated with lower vascularization scores (-0.005 [95%CI -0.009, -0.0001] 0.04) in male patients, but not in female patients. Males had higher sC5b-C9 compared to females. Additionally, males with high C5 had a higher synovial fluid concentration of sC5b-C9 compared to males with low C5. No differences were found in females.
Higher synovial fluid C5 levels were associated with increased complement activation and decreased synovial vascularization in males but not in females with OA. Future studies should test whether synovial fluid complement activation suppresses synovial angiogenesis and identify mechanisms accounting for C5-related sex-differences in synovial fluid complement activation in patients with knee OA.
膝关节骨关节炎（OA）的滑膜炎症导致滑液中滑膜血管生成和补体激活紊乱，但补体与滑膜微血管病理之间的联系尚未建立。由于补体在其他疾病中引起血管病理学变化，并且在补体激活和 OA 中存在性别差异，因此我们研究了晚期膝关节 OA 患者滑液中补体因子、滑膜组织血管病理学以及补体与滑膜血管病理学之间的相关性中的性别差异。
接受全膝关节置换术或胫骨高位截骨术的有症状、晚期影像学膝关节 OA 患者在手术期间提供了匹配的滑液和组织活检。通过多重或酶联免疫吸附试验分别测量滑液中的补体因子（C2、C5、脂联素、MBL 和 CFI）和末端补体复合物（sC5b-C9）。通过组织病理学评估滑膜血管病理学特征（血管化、血管周围水肿和血管病变）。使用多元线性回归模型来评估滑液补体因子与血管病理学特征之间的相关性，同时调整年龄、性别、体重指数和性别交互作用。完成了按性别划分的比较。
包括 97 名患者的滑膜液生物标志物和组织病理学数据。大多数滑液补体因子和滑膜组织组织病理学特征在性别之间相似。男性滑液 C5 水平趋于较低（-20.93ng/mL[95%CI-42.08，0.23]0.05）。男性的血管病变评分中位数（0.42[95%CI0.07，0.77]0.02）较高。在全队列中，C5 浓度与较低的血管化评分相关（-0.005[95%CI-0.010，-0.0001]0.04），同时考虑到性别*C5 相互作用。在按性别划分的分析中，在男性患者中，C5 浓度升高与血管化评分降低相关（-0.005[95%CI-0.009，-0.0001]0.04），而在女性患者中则没有。与女性相比，男性的 sC5b-C9 水平更高。此外，C5 水平较高的男性滑液中 sC5b-C9 浓度高于 C5 水平较低的男性。在女性中没有发现差异。
在男性 OA 患者中，较高的滑液 C5 水平与补体激活增加和滑膜血管生成减少相关，但在女性 OA 患者中则不相关。未来的研究应该检测滑液补体激活是否抑制滑膜血管生成，并确定导致膝关节 OA 患者滑液补体激活中与性别相关的 C5 差异的机制。
