Dramatic regulation of heparanase activity and angiogenesis gene expression in synovium from patients with rheumatoid arthritis

Abstract

Objective. Although heparanase is recognized as a proangiogenic factor, the involvement of heparanase in rheumatoid arthritis (RA) is unclear. In this study, we assessed heparanase activity in synovial fluid (SF) and synovial tissue (ST) from patients with RA or osteoarthritis (OA), and analyzed the expression of angiogenic pathway-focused genes in ST from RA and OA patients.Methods. SF and ST were obtained from the knees of patients with either RA or OA and from asymptomatic donors with no documented history of degenerative or inflammatory joint diseases. Heparanase activity was determined by an enzymatic assay using a radiolabeled substrate, and the presence of heparanase in ST was demonstrated by Western blotting. The expression of angiogenesis genes, including heparanase, in ST was analyzed by real-time quantitative polymerase chain reaction.Results. Heparanase activity was dramatically higher (>100-fold) in SF and ST from RA patients than in SF and ST from OA patients and asymptomatic donors. Active heparanase enzyme was detected and heparanase messenger RNA was up-regulated in ST from RA patients. We also found that angiogenesis gene expression was significantly regulated in RA synovium, and was correlated with heparanase activity.Conclusion. These findings are novel and contribute to our understanding of joint destruction in RA, suggesting that heparanase may be a reliable prognostic factor for RA progression and an attractive target for the treatment of RA.

Heparanase enhances myeloma progression via CXCL10 downregulation

“…Whether a similar mechanism is also exerted by heparanase in the framework of tumor progression is yet to be revealed. Noteworthy, heparanase activity is dramatically increased in patients with rheumatoid arthritis, and this induction was associated with a 2.5-fold decrease in CXCL10 42 , further strengthening the inverse correlation between heparanase and CXCL10 in the context of autoimmunity.…”

Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors

“…Moreover, up-regulation of heparanase has been found in the colonic epithelium of inflammatory bowel disease (IBD), 49 which in many aspects resembles gastrointestinal tract involvement in GVHD. Similarly, heparanase activity is dramatically elevated in sinovial fluid of patients with rheumatoid arthritis (RA), 50 further pointing to its possible role in chronic GVHD, which is an autoimmune disorder occasionally associated with arthralgia and sinovitis. In summary, our study demonstrates a strong correlation between the heparanase SNPs and the development of acute GVHD, suggesting an important role for heparanase in hyperactivation of donor T lymphocytes toward recipient tissues.…”

Old and new applications of non-anticoagulant heparin

“…Owing to the ubiquitous presence and multiple roles of HS, such as growth factor storage and activity, cytokines, chemokines and heparanase degrading activity, it is involved in several pathological conditions including inflammation, amyloidosis, diabetic and glomerular nephropathies, cancer metastasis and angiogenesis. Overexpression and enhanced local activity of heparanase were observed particularly in atherosclerosis [22], type 2 diabetes [23], inflammatory bowel disease [24], in synovial fluid from rheumatoid arthritis patients [25], as well as in kidneys from both diabetic nephropathic and glomerular disease patients [26]. The first clinical trial of low dose heparin (in combination) dates back to the 1960s, followed in 1971 by long term high dose heparin in chronic glomerular nephritis [26].…”