ORIGINAL ARTICLE Association of tumor necrosis factor–α (G-308A) genetic variant with matrix metalloproteinase–9 activity and joint destruction in early rheumatoid arthritis Sonja Stojanovic 1 & Bojana Stamenkovic 1 & Tatjana Jevtovic Stoimenov 2 & Jovan Nedovic 3 & Valentina Zivkovic 1 & Milena Despotovic 2 & Dusica Pavlovic 2 Received: 25 March 2017 /Revised: 17 May 2017 /Accepted: 22 May 2017 /Published online: 1 June 2017 # International League of Associations for Rheumatology (ILAR) 2017 Abstract Matrix metalloproteinases (MMPs) are the key en- zymes responsible for the joint destruction. Their activity is regulated by the level of proinflammatory cytokines. The aim of this study was to examine the impact of TNF–α G-308A polymorphism on MMP–9 levels in blood plasma (BP) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and their role in progression of joint destruction. One hundred thirty-four subjects were enrolled in this study. TNF–α G-308A polymorphism was determined using PCR–RFLP method. ELISA assay was used for the detection of MMP–9 activity in BP and SF. Joint damage was estimated by hands and feet radiography. Larsen score and annual changes in LS were used for quantitative evaluation of joint destruction and radiographic progression of disease. MMP–9 activity in BP and SF was significantly higher in RA compared to controls, as well as in SF of patients with erosive compared to nonerosive RA. Faster radiographic progression and increased MMP–9 activity in BP and SF were detected in the group A (GA or AA genotype carriers) compared to the group G (GG genotype carriers). However, statistical significance was re- vealed only for MMP–9 activity in SF (p < 0.05). MMP–9 activity in BP and SF is significantly higher in RA patients compared to patients with osteoarthritis. The presence of TNF–α-308A allele is associated with increased MMP–9 activity in SF of patients with early RA and may be a predictor of rapid radiographic progression of disease. Keywords Matrix metalloproteinase 9 . Rheumatoid arthritis . Single nucleotide polymorphism . Tumor necrosis factor–α Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown origin. The disease is characterized by the multi- factorial pathogenesis, variations in the clinical presentation of disease, and uncertain prognosis. The main characteristic of RA is persistent progressive and destructive synovitis. Proliferated synovia represents the tissue that invades cartilage and subchondral bone leading to their destruction (erosion), which is the main morphological outcome of inflammatory process in the joint [1]. Destruction of joint cartilage repre- sents an early stage in arthritis and its control is one of the therapeutic goals in RA. Cellular and molecular mechanisms of bone destruction are not completely understood. High levels of proinflammatory cytokines interleukin 1 (IL–1) and tumor necrosis factor α (TNF–α) are present in synovia of patients with different types of chronic arthritis. They disturb normal tissue homeo- stasis of cartilage and bone, activate osteoclasts, fibroblasts, and chondrocytes and increase the expression of matrix me- talloproteinases (MMPs), especially MMP–13, MMP–2, and MMP–9[2]. Some authors suggest that TNF–α induces in- creased expression of MMP–9 in RA, but the mechanisms involved in the regulation of this process are not completely understood [3, 4]. TNF–α influences MMP–9 production in dose- and time-dependent manner, suggesting that TNF–α induces increased expression and increased activity of * Sonja Stojanovic sonja.stojanovic1006@gmail.com 1 Institute BNiskaBanja^, Faculty of Medicine, University of Nis, Nis, Serbia 2 Department of Biochemistry, Faculty of Medicine, University of Nis, Nis, Serbia 3 Institute BNiskaBanja^, NiskaBanja, Serbia Clin Rheumatol (2017) 36:1479–1485 DOI 10.1007/s10067-017-3699-1