Synovitis as a Bystander or Potential Perpetuator of Cartilage Degradation in Osteoarthritis: Application of Tissue and Synovial Fluid Metrics Alongside Patient-Reported Assessments

Cartilage degradation is recognised as the primary site of lesions in the development of osteoarthritis (OA). It is characterised by a reduction in chondrocyte number, dysregulation of the cartilage-forming network, and depletion of key matrix components, such as proteoglycans, and collagenous and non-collagenous proteins. These changes in cartilage composition can be detected in synovial fluid as varying levels of cartilage turnover byproducts, including the C-terminal cross-linked telopeptide of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP). Emerging as a secondary response, synovitis subsequently causes degradation of articular cartilage, mediating the release of proinflammatory factors, including nuclear factor kappa B (NF-kB). Despite extensive research, the direct role of synovitis in exacerbating cartilage degradation remains not fully elucidated.
The objective of this study is to explore the relationship between synovial inflammation, cartilage degradation, and patient-reported outcomes in OA, with a particular focus on how synovitis influences chondrocyte numbers, cartilage matrix composition, and biomarkers such as synovial fluid CTX-II and COMP, as potential indicators of joint involvement and local inflammation.
Thirty-five adults with clinically and radiologically confirmed late-stage primary OA of the knee who underwent joint replacement surgery were enrolled in the study. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and stiffness subscales were applied to all patients prior to surgery. Synovial membrane, cartilage, and synovial fluid samples were obtained during the surgical intervention. The collected tissue samples were processed routinely and stained with haematoxylin and eosin, and toluidine blue. Based on histopathologically confirmed synovitis, graded according to the Krenn system, patients were divided into two groups: those with observed synovitis (synovitis group) and those without observed synovitis (no-synovitis group). Additionally, NF-κB expression in the synovial membrane was assessed immunohistochemically and quantified. Cartilage degradation severity was assessed using the Osteoarthritis Research Study Initiative (OARSI) cartilage histopathological score, alongside quantitative evaluation of chondrocytes and chondrocyte clusters, and semi-quantitative assessment of cartilage cellularity. Proteoglycan content in the cartilage was assessed semi-quantitatively based on the staining intensity of toluidine blue. Levels of CTX-II and COMP were measured using an ELISA assay. Statistical data analysis was conducted using SPSS 28.0. Statistical significance was set at p<0.05.
The synovitis group exhibited low-grade inflammation, a mild increase in the thickness of the lining layer, and increased cellularity in the sublining layer compared to the no-synovitis group (p<0.001). A significant overexpression of NF-κB was observed in the synovial membrane of the synovitis group compared to the no-synovitis group (p=0.006). The OARSI score was higher in the synovitis group than in the no-synovitis group, showing delamination in the superficial cartilage zone in the synovitis group and vertical fissures in the no- synovitis group (p=0.047). A moderate correlation was found between synovitis and cartilage degradation severity (r=0.474, p=0.022). In the synovitis group, there was a trend towards fewer chondrocytes and chondrocyte clusters compared to the no-synovitis group, although the difference was not significant.
Proteoglycan staining was low grade in both study groups, suggesting depleted proteoglycan levels within the cartilage. In the synovitis group, median CTX-II levels in synovial fluid were lower than in the no-synovitis group, with values of 0.813 ng/ml and 1.085 ng/ml, respectively. Simultaneously, median COMP levels in synovial fluid were significantly higher in the synovitis group compared to the no-synovitis group, with values of 1333.375 ng/ml and 1088.250 ng/ml, respectively (p=0.036). WOMAC-assessed pain was higher in the synovitis group than in the no-synovitis group (p=0.050). Similarly, WOMAC-assessed stiffness was more intense in the synovitis group than in the no-synovitis group (p=0.011).
The results of this study suggest that the presence and extent of inflammation are associated with increased cartilage degradation in OA, as well as worsening clinical signs, including pain and stiffness. The reduction in chondrocyte numbers indicates impaired cartilage regeneration in the presence of synovitis. Additionally, the lower levels of synovial fluid CTX-II in the synovitis group point to increased cartilage deterioration. The observed increase in synovial fluid COMP levels, alongside the severity of synovitis, may indicate its potential as a marker reflecting both cartilage degradation and local inflammation.