Background/Purpose: Obesity is a major risk factor for poor outcomes in knee osteoarthritis (OA) and may involve both mechanical and physiological stresses on joint tissues. In the synovium, macrophages and fibroblasts are important for maintaining joint homeostasis and adaptive responses to joint stressors. However, the impact of obesity on synovial cellular mechanisms are not well understood. Our objectives were 1) to investigate the association of obesity and synovial histopathological features, and 2) to explore the effect of obesity on synovial cell gene expression in people with knee OA.

Methods: Patients (n=107) diagnosed with clinical knee OA based on the American College of Rheumatology (ACR) criteria were included in this cross-sectional analysis. All patients had severe symptoms and radiographic damage (KL grade 3 or 4), and were undergoing surgery for knee OA. Lateral suprapatellar synovial tissue biopsies were obtained during surgery. Routine synovial histopathology was scored (grade 0-3; None-Severe) in six domains. Multivariate linear regression was used to evaluate the association between median histopathology component scores and BMI, while adjusting for age and sex. Single cells dissociated from whole synovium biopsies were sorted into CD14+ (macrophage/monocyte) and CD90+ (stromal) cell compartments for RNA isolation and sequencing. Quantification of genes was performed in featureCounts and DESeq2 was used to normalize counts. Gene set enrichment was assessed using mSigDB Hallmark gene sets between patients with BMI < 30kg/m² (n=7) and BMI >35kg/m² (n=6).

Results: Elevated BMI was associated with lower median synovial vascularization (β = -1.35, [95%CI -2.43, -0.27]) and fibrin deposition (β = -3.80, [95%CI -6.98, -0.62]) histopathology scores. In normal to overweight patients (BMI < 30kg/m² ), CD14+ macrophage gene expression showed significant enrichment scores for immune cell signaling (e.g. TNF-α signaling, IFN-γ and IFN-α response, IL6/JAK/STAT3 signaling) and cell metabolism pathways (e.g. fatty acid metabolism, adipogenesis, oxidative phosphorylation, mTOR signaling). CD90+ stromal cell gene expression also showed significant enrichment scores for response to pro-inflammatory signaling pathways and cell metabolism pathways. In obese patients (BMI >35kg/m²), synovial macrophage and stromal cell compartments both showed enrichment of cell stress and degenerative pathways (e.g. p53 pathway, unfolded protein response, apoptosis, hypoxia, epithelial-mesenchymal transition, hedgehog signaling, Wnt/β-catenin signaling, TGF-β signaling).

Conclusion: Obesity was associated with reduced signs of inflammation in synovial tissues (vascularization and fibrin), and with less inflammatory signaling, impaired cellular metabolism, and greater cellular stress in synovial macrophages and stromal cells. Our results suggest synovial inflammation and vascularization may be adaptive responses to OA-related joint stresses, and that obesity may impair these adaptive synovial processes.

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/synovial-cell-dysfunction-in-obese-patients-may-contribute-to-poor-outcomes-in-knee-osteoarthritis/