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Abstract
A full understanding of the molecular mechanisms implicated in the etiopathogenesis of juvenile idiopathic arthritis (JIA) is lacking. A critical role for leukocyte proteolytic activity (e.g., elastase and cathepsin G) has been proposed. While leukocyte elastase’s (HLE) role has been documented, the potential contribution of proteinase 3 (PR3), a serine protease present in abundance in neutrophils, has not been evaluated. In this study we investigated: (1) PR3 concentrations in the synovial fluid of JIA patients using ELISA and (2) the cartilage degradation potential of PR3 by measuring the hydrolysis of fluorescently labeled collagen II in vitro. In parallel, concentrations and collagen II hydrolysis by HLE were assessed. Additionally, the levels of the co-secreted primary granule protein myeloperoxidase (MPO) were assessed in synovial fluid of patients diagnosed with JIA. We report the following levels of analytes in JIA synovial fluid: PR3—114 ± 100 ng/mL (mean ± SD), HLE—1272 ± 1219 ng/mL, and MPO—1129 ± 1659 ng/mL, with a very strong correlation between the PR3 and HLE concentrations (rs = 0.898, p < 1 × 10–6). Importantly, PR3 hydrolyzed fluorescently labeled collagen II as efficiently as HLE. Taken together, these novel findings suggest that PR3 (in addition to HLE) contributes to JIA-associated joint damage.
Highlights
Juvenile idiopathic arthritis (JIA) is an umbrella term used to describe a group of heterogenous conditions characterized by chronic arthritis of an unknown etiology, lasting more than six weeks, with onset before the 16th birthday [1]
Fifteen of the 18 subjects were female, though since JIA occurs at roughly twice the rate in females compared to males [20,21], this is within expectations
Eleven subjects had oligoarthritis and seven polyarthritis rheumatoid factor (RF)-negative; 14/19 samples were collected from a right knee aspirate
Summary
Juvenile idiopathic arthritis (JIA) is an umbrella term used to describe a group of heterogenous conditions characterized by chronic arthritis of an unknown etiology, lasting more than six weeks, with onset before the 16th birthday [1]. JIA is a chronic disease characterized by prolonged synovial inflammation that may cause structural joint damage. JIA subtypes, all share an autoimmune inflammatory process that inundates the joint with white blood cells, predominantly neutrophils [4,5]. Neutrophils (PMNs) are the most abundant and the first immune cells to reach the joint. They carry intracellular granules containing large quantities of proteases such as proteinase 3 (PR3) and leukocyte elastase (HLE), as well as enzymes such as myeloperoxidase (MPO), used to destroy engulfed pathogens. During PMN degranulation or NETosis [10], these enzymes are released into the extracellular space where they can damage host tissue
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