Abstract
Immune cell migration from the bloodstream to target tissues is a hallmark of rheumatoid arthritis (RA) pathogenesis. The role of chemoattractants, mainly chemokines, and their possible targeting for therapeutic purposes have been under intense investigation over the last few years but the results were not as satisfactory as expected. The insulin-like growth factor binding protein 6 (IGFBP6), a direct inhibitor of insulin-like growth factor (IGF)-II, also exerts IGF-independent effects including tumor cell migration in vitro. We aimed to assess the expression of this protein in serum, synovial fluid, and synovial tissue (ST) of RA patients and to identify its possible chemotactic role in this disorder. IGFBP6 was measured in RA patients and healthy donors (HD) sera by Luminex xMAP® technology and in ST of RA patients and osteoarthritis (OA) controls by immunofluorescence. The identification of circulating IGFBP6+ cells was evaluated by flow cytometry and an in vitro migration assay was arranged. We demonstrated that IGFBP6 is able to induce greater in vitro migration of RA as compared to HD and OA T lymphocytes and is overexpressed in serum and ST of RA patients. This in vitro chemotactic activity can be partially inhibited by dexamethasone. Our findings suggest a pathogenic role of IGFBP6 in RA and support its possible targeting for therapeutic purposes.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that predominantly affects the joints
Since insulin-like growth factors (IGFs) are thought to be involved in the maintenance of articular cartilage and bone homeostasis, in part through their ability to reverse the catabolic effects mediated by pro-inflammatory cytokines, a number of studies tried to analyze their role in rheumatoid synovitis
We first sought to investigate the concentration of insulin-like growth factor binding protein 6 (IGFBP6) in the serum of RA patients and we found that it was significantly increased compared to healthy donors (HD) (Figure 1A)
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that predominantly affects the joints. An excessive migration of these cells and their retention in the synovial environment, together with impaired apoptotic processes, chronically maintain the inflammatory response with the development of hyperplastic synovium and neoangiogenic phenomena. Rheumatoid synovial pannus can lead to damage of articular cartilage and bone with progressive joint destruction [1]. Cartilage and bone damage in RA may be considered the final result of catabolic mechanisms in the joint space exceeding anabolic pathways, similar to what occurs in tumor development and invasion. Since insulin-like growth factors (IGFs) are thought to be involved in the maintenance of articular cartilage and bone homeostasis, in part through their ability to reverse the catabolic effects mediated by pro-inflammatory cytokines, a number of studies tried to analyze their role in rheumatoid synovitis.
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