Abstract
Osteoarthritis (OA) is a progressive joint disease driven by a blend of inflammatory and biomechanical processes. Studies using human samples to understand inflammatory mechanisms in OA frequently recruit OA patients with different affected joints, even though recent evidence indicates that OA is a heterogeneous disease which only culminates in a common end point. Differences in age of onset and the dynamics of disease progression suggest that different joints may represent different disease entities, thereby diluting the discovery potential in a combined analysis. We hypothesized that different OA joints may also differ in immunopathology within the synovium. To investigate this hypothesis, we profiled the immune cell contribution (flow cytometry) and cytokine release profiles (ELISA) in purified synovial membrane mononuclear cells from 50 patients undergoing either hip (n = 34) or knee (n = 16) replacement surgery. Unsupervised computational approaches were used for disease deconstruction. We found that hip and knee osteoarthritis are not identical in respect to the inflammatory processes that take place in the synovial membrane. Instead, we report that principally CD14+ macrophages are expanded fourfold in the synovial membrane of patients with knee OA compared to hip OA, with a trend to higher expression in CD8+ T cells, while CD4+ T cells, B cells, and NK cells were found at comparable quantities. Upon isolation and culture of cells from synovial membrane, isolates from hip OA released higher concentrations of Eotaxin (CCL11), G-CSF, GM-CSF, INF-γ, IP-10 (CXCL10), TNF-α, MIP-1α (CCL3), MIP-1β (CCL4), IL-4, IL-10, IL-17, and lower concentrations of stem cell factor (SCF), thereby highlighting the difference in the nature of hip and knee osteoarthritis. Taken together, this study establishes hip and knee OA as immunologically distinct types of OA, and creates a resource of the cytokine expression landscape and mononuclear cell infiltration pattern of patients with hip and knee osteoarthritis.
Highlights
Osteoarthritis (OA) is a heterogeneous disease, and with a prevalence of symptomatic OA of 10% in men and 18% in women aged over 60, represents the most frequent cause of disability in older adults according to the World Health Organization [1]
The two study groups showed significant differences regarding the demographic parameters age at surgery and BMI (Table 1): Hip OA patients were significantly younger, while the average BMI was significantly higher in knee than hip OA (knee OA)
The laboratory parameters C-reactive protein (CRP) and leucocytes were within standard range, and did not suggest any signs of systemic inflammation at the time of surgery
Summary
Osteoarthritis (OA) is a heterogeneous disease, and with a prevalence of symptomatic OA of 10% in men and 18% in women aged over 60, represents the most frequent cause of disability in older adults according to the World Health Organization [1]. OA was traditionally viewed as a non-inflammatory joint disease with ageing, with mechanical stress being considered the major contributors to cartilage breakdown and bone remodeling. This still being relevant, evidence for an inflammatory component to OA pathogenesis is significantly increasing [3,4,5]. Infiltrating immune cells use soluble mediators to communicate with resident cells, the two predominant inflammatory cytokines being IL-1β and TNF-α [2]. IL-17 is another central cytokine in joint inflammation It is secreted by Th17 cells in response to IL-23 and sustains inflammation by supporting production of further inflammatory cytokines and attracting influx of more immune cells, for example neutrophils. Inflammatory mediators are implied in OA pathophysiology, and immunological mechanisms in OA are fundamental to study, but still far from understood
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