Purpose: Synovial inflammation (synovitis) and aberrant joint loading are important, related risk factors for knee osteoarthritis (OA) incidence and progression. OA-related synovitis is associated with vascular pathology, including neovascularization and perivascular edema. We recently demonstrated that synovial perivascular edema, a key feature of physiologic tissue stress, is associated with aberrant joint loading during walking. However, the mechanisms by which abnormal joint loading induces synovial perivascular edema are unknown. Identifying mechanisms of vascular dysfunction in OA synovium may lead to treatments that mitigate the pathological effects of physiologic joint stress caused by biomechanical loading. The objective of this study was to investigate candidate mechanisms between surrogate measures of dynamic knee load during gait and synovial perivascular edema, including increases in synovial angiogenesis and/or angiogenic factors that cause endothelial stress/dysfunction such as placental growth factor (PlGF) and endoglin.
Methods: Patients (n = 98) undergoing total knee arthroplasty or high tibial osteotomy for symptomatic, radiographic knee OA were included in this cross-sectional study. Study participants underwent 3D gait analysis within 12 weeks prior to surgery. Inverse dynamics were used to calculate external knee moments in the sagittal, frontal, and transverse planes. Lateral, supra-patellar synovial tissue biopsies and synovial fluid were obtained intra-operatively. Synovial tissue underwent detailed histopathological measurement to quantify microvessel density (MVD) and the density of microvessels with perivascular edema (edemic MVD) per synovial tissue area (vessels/mm2). Synovial fluid concentrations of endoglin and PlGF were measured by multiplex assay. We used multivariate linear regression models adjusting for age, sex, BMI, and gait speed to investigate associations between external knee moments with synovial MVD and/or edemic MVD, and with synovial fluid endoglin and PlGF concentrations in a sub-group of patients (n = 80) with adequate, high-quality synovial fluid available for factor measurement. Statistical models were constructed using Graphpad Prism 9 (Version 9.2.0) Results include unstandardized β coefficients with 95% confidence intervals (CIs).
Results: Our cohort was composed of a roughly equal number of male and female patients with predominately late-stage knee OA (Table 1). The 1st peak knee adduction moment (KAM) (β= 0.54 vessels/mm2 [95%CI 0.24, 0.84]), KAM impulse (β= 0.74 vessels/mm2 [95%CI 0.34, 1.13]) and peak internal rotation moment (β= 1.08 vessels/mm2 [95%CI 0.14, 2.02]) were associated with increased edemic MVD (Table 2). The KAM impulse was also associated with increased synovial MVD (β= 0.70 vessels/mm2 [95%CI 0.02, 1.39]) (Table 2). The associations between edemic MVD and 1st peak KAM (β= 0.44 vessels/mm2 [95%CI 0.17, 0.70]), KAM impulse (β= 0.55 vessels/mm2 [95%CI 0.19, 0.91]) and peak internal rotation moment (β= 0.98 vessels/mm2 [95%CI 0.16, 1.80]) were reduced, but remained when adjusting for synovial MVD, indicating partial mediation (Table 2). The KAM impulse was associated with increased synovial fluid endoglin (β= 2.49 pg/ml [95%CI 0.18, 4.79]) and PlGF (β= 1.49 pg/ml [95%CI 0.46, 2.53]) concentrations (Table 3).
Conclusions: We found that proxy measures of dynamic knee load during gait are associated with synovial vascular pathology in patients with late-stage knee OA. This study used quantitative measures of synovial microvessels and confirms our earlier finding of an association between dynamic knee load and the presence of synovial perivascular edema. Further, these new data suggest that increased angiogenesis and synovial fluid levels of angiogenic factors that cause endothelial dysfunction are potential mechanisms leading to perivascular edema associated with dynamic knee load. Together, these data support the general hypothesis that biomechanical loading of structural joint tissues leads to cross-talk with the synovium in patients with knee OA, and links mechanical loading to synovial vascular pathology.
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