Abstract
This study was performed to evaluate the effects of 15-month anti-tumor necrosis factor α (anti-TNF-α) therapy on the aggrecan turnover of female rheumatoid arthritis (RA) patients. Serum was obtained from healthy subjects and female RA patients treated with TNF-α inhibitors (TNFαI) in combination with methotrexate. We measured serum levels of aggrecan chondroitin sulfate 846 epitope (CS846), aggrecan fragments (AGC), disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and 5 (ADAMTS-5), as well as their natural inhibitor, known as tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), using immunoassay methods. Serum levels of CS846, AGC, ADAMTS-4, ADAMTS-5 and TIMP-3 were higher in female patients with RA before the treatment in comparison to healthy subjects. Ratio of ADAMTS-5 to TIMP-3 was significantly higher in RA women than in controls, whereas ADAMTS-4/TIMP-3 ratio did not differ from that in controls. During the anti-TNF-α therapy, the serum levels of 846 epitope increased, whereas levels of AGC decreased in female RA patients. Furthermore, 15 months of treatment with TNFαI downregulated serum levels of both ADAMTS, without any effect on TIMP-3 levels. These changes were accompanied by significantly reduced ratios of ADAMTS to TIMP-3. According to our results, anti-TNF-α therapy has a beneficial impact on aggrecan remodeling during RA.
Highlights
Rheumatoid arthritis (RA) is the most common chronic autoimmune inflammatory arthritis, affecting approximately 1% of the adult population worldwide
Our study demonstrates that effective 15-month anti-inflammatory treatment with tumor necrosis factor α (TNF-α) inhibitors (TNFαI) was associated with improvement of aggrecan turnover, assessed through serum levels of aggrecan-derived synthesis and degradation molecules (CS846 and aggrecan fragments (AGC), respectively) and ADAMTS levels in female RA patients
Since the 846 epitope is expressed only on the largest, newly synthesized aggrecan molecules, it may be suggested that the increased levels of chondroitin sulfate 846 epitope (CS846) that we found in all RA patients treated with TNFαI may be a reparative response of the chondrocytes
Summary
Rheumatoid arthritis (RA) is the most common chronic autoimmune inflammatory arthritis, affecting approximately 1% of the adult population worldwide. Among mechanisms involved in joint damage, pro-inflammatory cytokines, notably tumor necrosis factor α (TNF-α) and interleukin (IL)-1β, play a crucial role in the initiation and perpetuation of the synovial inflammation and cartilage extracellular matrix (ECM) breakdown [2,3,4]. The latter one is synthesized by highly specialized mesenchymal cells called chondrocytes and is composed primarily of water molecules and type II collagen fibrous network, which entraps negatively charged proteoglycans (PGs) [4,5]. The major PG in articular cartilage is aggrecan, a large aggregating
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