Abstract
Objective: Previous study demonstrated the involvement of basic aminopeptidase (APB) activity in the development of collagen-induced arthritis (CIA). Two zinc dependent metalloenzymes (EC 3.4.11.6 and EC 3.3.2.6) are known to exhibit concomitantly APB and leukotriene-A4-hydrolase (LT-A4-H) activities. Influence of the interrelationship between both activities on arthritic processes, however, is presently uncertain. This study aimed to compare these activities in CIA. Methods: CIA was induced in rats and arthritis was assessed macroscopically. Ultracentrifugation was used to separate soluble (S) and solubilized membrane-bound (M) fractions from peripheral blood mononuclear cells (PBMCs) and synovial tissue (ST). Enzyme immunoassay was used to measure LT-A4-H activity, and Real Time Polymerase Chain Reaction was used for evaluating EC 3.4.11.6 and EC 3.3.2.6 gene expressions. Results: The existence of genes for EC 3.3.2.6 and EC 3.4.11.6 was demonstrated in the ST. Compared with control, LT-A4-H activity increased in synovial fluid (SF) and in S-PBMCs of CIA-arthritic and CIA-resistant and in M-ST of CIA-resistant, while it decreased in M-PBMCs of CIA-arthritic and CIA-resistant. In all these locations APB activity remained unchanged or inversely correlated with LT-A4-H activity. Conclusions: LT-A4-H and APB activities in joint-related samples are associated, for the first time, with EC 3.3.2.6 and EC 3.4.11.6 genes, exhibiting a compartment-dependent differential modulation of their specificity, efficiency and/or affinity or an inverse concurrent pattern. Changes in LT-A4-H activity have implications for development or resistance to arthritis in CIA model with a potential to be a diagnostic tool.
Highlights
Rheumatoid arthritis (RA) is characterized by peripheral polyarthritis with cartilage and bone erosions, resulting in deformity and joint destruction [1]
These data agree with the differential detection of serum TNF-α levels and histopathological alterations of the tibio-tarsal joint in the CII treated animals that develop severe edema (CIA-arthritic), which can be confidentially distinguished from collagen-induced arthritis (CIA)-resistant [28,29]
Based on the macroscopic classification of edema formation, preconized by Erlandsson Harris et al [39], all arthritic animals selected here had the maximum score in hind paws. 10% of CII treated animals were discarded because they did not reach this level of arthritis
Summary
Rheumatoid arthritis (RA) is characterized by peripheral polyarthritis with cartilage and bone erosions, resulting in deformity and joint destruction [1]. This process is associated with inflammatory hyperplasia of the synovial membrane, known as pannus [2]. The arthritis induced by CII (CIA) [4,5,6,7,8,9] generates an erosive polyarthritis [5,8,10] that has been intensively studied due to its similarities with the RA [4,6,9,10,11], mainly regarding the development of synovitis, progressive pannus formation, marginal erosion of bone and cartilage destruction [4,6,8]. Two zinc dependent metalloenzymes [15,16,17,18], leukotriene (LT)-A4 hydrolase (LT-A4-H) (EC 3.3.2.6) and basic aminopeptidase (APB) (EC 3.4.11.6), seem to exhibit concomitant hydrolytic activities on L-arginyl-β-naphthylamide (ArgNA) and on LT-A4 [18,19,20,21,22,23]
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