Background: Recent data have shown that enhanced cytokine production in knee osteoarthritis (OA) synovium are believed to promote pathological OA. High-mobility group box 1 (HMGB-1) as a well-known pro-inflammatory cytokine may influence the development of knee OA. The purpose of this study is to analyze the amount of and location of HMGB-1 in OA synovium and to compare it with controls who are afflicted with acute meniscal or cruciate ligament tears. We also evaluated the relationship between the level of HMGB-1 in synovial fluid with the severity of synovitis, clinical symptoms (pain, stiffness, daily activity), and radiological changes in patients with knee OA.
Methods: Synovium and synovial fluid were harvested from seventy-four knee OA patients and thirty-four controls afflicted with acute meniscal or cruciate ligament tears. Kellgren-Lawrence (KL) grading system and Western Ontario McMaster University Osteoarthritis Index (WOMAC) assessment scale were applied to evaluate the radiological and clinic severity of OA patients. Additionally, for all patients, the microscopic synovitis was graded to evaluate the severity of synovium pathology. The location of HMGB-1 was determined in the synovium by immunohistochemistry. Synovium and synovial fluid HMGB-1 levels were measured by western blotting and enzyme-linked immunosorbent assay (ELISA), respectively.
Results: Synovium immunohistochemical analysis revealed that HMGB-1 displayed a strictly nuclear localization in controls; however, both nuclear and cytoplasmic distributions were present in OA patients. The percentage of HMGB-1 positive cells as well as cytoplasmic HMGB-1 cell population in OA patients were higher than those of controls (42.5% vs. 39.7% and 24.0% vs. 5.7%). Both synovium and synovial fluid HMGB-1 levels in OA patients were significantly higher than controls. In OA patients, HMGB-1 in the KL2/3 group was higher than in the KL4 group. Additionally, synovial fluid HMGB-1 levels in OA patients were positively associated with the severity of synovitis, pain, and daily activities.
Conclusions: Our results demonstrated that HMGB-1 is overexpressed and relocated in synovial membranes of patients with knee OA. The increased synovial fluid HMGB-1 levels were associated with the severity of synovitis, pain, and daily activities in knee OA patients. These results suggested that HMGB-1, as a pro-inflammatory cytokine, may play a crucial role in the progression of knee OA.