Synovial Inflammation as an Essential Feature of Osteoarthritis: Unravelling the Role of Viral Agents and Associations with Cognitive and Mental Health Outcomes. Doctoral Thesis

Abstract

Osteoarthritis (OA) remains the most prevalent joint disorder worldwide, particularly affecting individuals over the age of 50. Although numerous pathogenetic mechanisms contribute to the initiation and progression of articular cartilage degeneration, synovial inflammation plays a significant role in the disease process. While the degree of inflammation in OA is less pronounced and not systemic as seen in inflammatory arthritides, its involvement constitutes a critical element in the pathogenesis, progression, and persistence of the disease. The effects of synovial inflammation extend beyond the stimulation of catabolic processes, encompassing the acceleration of cellular senescence and potential contributions to neuropsychiatric disturbances, including mood and cognitive alterations. While inflammation in OA has been previously investigated, the complex and multifactorial nature of its triggers, such as latent viral infections, requires further study. Moreover, the potential associations between synovial inflammation and depressive symptoms or cognitive decline remain insufficiently understood and warrant comprehensive investigation. In this study, two independent cohorts of 54 and 50 individuals undergoing joint replacement surgery were analysed. In the first cohort, a focused investigation on the persistence of parvovirus B19 (B19V) and human herpesvirus 7 (HHV-7) in the synovial membrane and their potential impact on inflammation was conducted using the Krenn synovitis histological scoring system. Immunohistochemical analyses were performed to evaluate the expression of tumour necrosis factor alpha (TNF-α) and transforming growth factor-beta (TGF-β) in synovial tissue and to investigate their association with viral presence. Nonetheless, HHV-7-positive samples showed a significant correlation between CD4+ lymphocyte infiltration and TNF-α expression, suggesting immune cell-specific responses to latent viral presence. Additionally, the role of S100 protein expression in the inflammatory process was assessed, showing a positive correlation. This integrative approach aimed to elucidate the contribution of chronic viral persistence and local immune responses to the synovial pathology observed in OA. The second cohort was evaluated for synovial inflammation and its correlation with urinary biomarkers, using ELISA method: C-telopeptide of type II collagen (CTX-II), cartilage oligomeric matrix protein (COMP), TNF-α, TGF-β1 and neuropsychological assessments, including Montreal Cognitive Assessment (MoCA), Patient Health Questionnaire-9 (PHQ-9), and Generalised Anxiety Disorder-7 (GAD-7) tests. In the second cohort, histologically confirmed synovitis scores varied widely and correlated with urinary TGF-β1 levels. Cognitive (MoCA) and affective (PHQ-9, GAD-7) scores showed significant associations with synovial inflammation, particularly in patients with moderate-to-high inflammatory grades. Cluster analysis revealed distinct inflammatory phenotypes with gender-linked variations in symptom severity and cognitive and affective symptom outcomes.