Sex-Differences and Associations Between Complement Activation and Synovial Vascularization in Patients with
Emily U Sodhi1, Holly T Philpott2,3, McKenzie M Carter1,3
1Department of Physiology & Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Insights
In knee osteoarthritis, higher C5 complement levels correlate with reduced blood vessel formation in males, but not females. This suggests sex-specific roles for complement in synovial angiogenesis.
Area of Science:
- Immunology
- Orthopedics
- Vascular Biology
Background:
- Synovial inflammation in knee osteoarthritis (OA) involves disorganized angiogenesis and complement activation.
- The relationship between complement factors and synovial microvascular pathology in OA remains unclear.
- Sex differences in complement activation and OA prevalence suggest potential sex-specific mechanisms.
Purpose of the Study:
- To investigate sex differences in synovial fluid complement factors and vascular pathology in late-stage knee OA.
- To determine associations between complement factors and synovial vascular pathology, considering sex interactions.
Main Methods:
- Collected synovial fluid and tissue from 97 patients undergoing knee surgery for OA.
- Measured complement factors (C2, C5, adipsin, MBL, CFI) and terminal complement complex (sC5b-C9) in synovial fluid.
- Assessed synovial vascular pathology (vascularization, edema, vasculopathy) via histopathology.
- Used multivariate regression models with sex interaction terms to analyze associations.
Main Results:
- Synovial fluid C5 levels trended lower in males; vasculopathy scores were higher in males.
- In the full cohort, C5 concentration was linked to lower vascularization.
- In males, higher C5 was associated with lower vascularization, but this was not observed in females.
- Males exhibited higher sC5b-C9 levels than females.
Conclusions:
- Elevated synovial fluid C5 is associated with increased complement activation and reduced synovial vascularization in males with knee OA.
- These findings highlight potential sex-specific roles of complement in OA pathogenesis.
- Further research is needed to elucidate the mechanisms behind C5-related sex differences in complement activation and synovial angiogenesis.
Purpose:
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.
Methods:
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.
Results:
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] p=0.05). Median vasculopathy scores (0.42 [95%CI 0.07, 0.77] p=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] p=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] p=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.
Conclusion:
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.
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