Proinflammatory mediators and gene polymorphism of ММР1 and ММР12 in post-traumatic knee osteoarthritis.

Abstract

Joint injury is a well-established risk factor for development of post-traumatic knee osteoarthritis (PTOA) and may lead to joint inflammation. The aims of the study were: the investigation of proinflammatory mediators - the levels of IL-1β and uric acid (UA), the activity of xanthine oxidoreductase (XOR) - in the plasma and synovial fluid (SF) of patients with PTOA; the search for putative predictors of progression and predisposition to the PTOA development among these mediators and polymorphic gene loci of matrix metalloproteinases (MMP) - rs1799750 ММР1 and rs2276109 ММР12. Patients with a radiographically diagnosed PTOA (Kellgren-Lawrence, K/L grades I-III, N = 71) and 44 healthy controls were enrolled in the study of the levels of proinflammatory mediators. The XOR activity was measured by quantitation of uric acid accumulation at 293 nm as a result of xanthine oxidation. The uric acid level was determined using a commercially available kit (“Vital”, Russia) and spectrophotometer. The level of IL-1β was measured using commercially available enzyme-linked immunosorbent assay (ELISA) kit (“Vector-Best”, Russia) according to the manufacturers’ instructions. We used PCR followed by agarose gel electrophoresis (“SNP-Express” kits, “Lytech”, Russia) for SNP-genotyping. The XOR activity, the levels of proinflammatory mediators uric acid and IL-1β were determined to be significantly increased in the plasma of PTOA patients - by 20% (p = 0,03), 49% (p = 0,009) and 41% (p = 0,044), respectively. Multiple regression adjusted for age, gender, BMI of patients showed that xanthine oxidase activity was a significant predictor of radiographic knee osteoarthritis (β = 0,373, p < 0,01). Genetic analyses of 184 patients with PTOA and 113 healthy controls demonstrated that G-allele of polymorphic locus A-82G ММР-12 was associated with higher risk of post-traumatic knee osteoarthritis development (OR = 1,803, p = 0,028). The -82G-allele of ММР-12 may abrogate angiostatic effect of MMP-12 by decreasing its expression and promote activated macrophage recruitment and degradation of the cartilage.