Abstract
Hemophilic arthropathy (HA) typically begins with proliferative synovitis that shares some similarities with inflammatory arthritides, in which the proinflammatory cytokine tumor necrosis factor (TNF)-α has a crucial pathogenetic role. Inappropriate release of TNF-α was shown to contribute to arthropathy development following intra-articular bleeding in hemophilic mice. Here, we were interested in determining whether systemic levels of TNF-α and synovial tissue expression of the TNF-α/TNF receptor (TNF-R) system could be increased and related to joint damage in hemophilia A patients with severe HA. Serum levels of TNF-α measured by quantitative enzyme-linked immunosorbent assay (ELISA) were significantly increased in HA patients (n = 67) compared to healthy controls (n = 20). In HA patients, elevated TNF-α levels were significantly associated with the number of hemarthroses, the grade of synovial hypertrophy, and both the clinical World Federation of Hemophilia score and ultrasound score. The expression of TNF-α, TNF-R1, and TNF-R2 was strongly increased in HA synovium (n = 10) compared to the non-inflamed osteoarthritis control synovium (n = 8), as assessed by both immunohistochemistry and Western blotting. Increased protein levels of TNF-α, TNF-R1, and TNF-R2 were retained in vitro by HA fibroblast-like synoviocytes (n = 6) with respect to osteoarthritis control fibroblast-like synoviocytes (n = 6). Stimulation with TNF-α resulted in a significant increase in HA fibroblast-like synoviocyte proliferation quantified by the water-soluble tetrazolium (WST)-1 assay, while it had no relevant effect on osteoarthritis fibroblast-like synoviocytes. Quantification of active/cleaved caspase-3 by ELISA demonstrated that TNF-α did not induce apoptosis either in HA or in osteoarthritis fibroblast-like synoviocytes. The TNF-α/TNF-R system may represent a crucial mediator of proliferative synovitis and, therefore, a new attractive target for the prevention and treatment of joint damage in HA patients. Our findings provide the groundwork for further clinical investigation of anti-TNF-α therapeutic feasibility in hemophiliacs.
Highlights
Intra-articular bleeding plays a pivotal role in the pathogenesis of hemophilic arthropathy (HA), a major clinical manifestation of hemophilia characterized by large-joint synovitis evolving into articular cartilage destruction and subchondral bone resorption that frequently results in osteopenia or osteoporosis [1,2,3,4,5,6,7]
Since the aforementioned data indicate that abnormal tumor necrosis factor (TNF)-α release may represent a potential new target to prevent bone resorption following a joint bleed in mice, we aimed at determining whether systemic levels of TNF-α and synovial tissue expression of this proinflammatory cytokine and its receptors could be increased and related to the development of proliferative synovitis in hemophilia A patients with severe HA
No significant differences in serum TNF-α levels were detected according to the HCV-RNA, anti-HCV, or HIV status of HA patients
Summary
Intra-articular bleeding plays a pivotal role in the pathogenesis of hemophilic arthropathy (HA), a major clinical manifestation of hemophilia characterized by large-joint synovitis evolving into articular cartilage destruction and subchondral bone resorption that frequently results in osteopenia or osteoporosis [1,2,3,4,5,6,7]. Gene expression analysis revealed increased synovial fluid levels of multiple proinflammatory mediators, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, while plasma analysis demonstrated significantly increased systemic levels of IL-6 [14] Another recent study focusing on the detailed mapping of the early HA pathogenesis through a time-course study of induced hemarthrosis in hemophilic rats revealed proliferative synovitis dominated by neutrophil and macrophage infiltration that develops within hours after hemarthrosis [15]. Since the aforementioned data indicate that abnormal TNF-α release may represent a potential new target to prevent bone resorption following a joint bleed in mice, we aimed at determining whether systemic levels of TNF-α and synovial tissue expression of this proinflammatory cytokine and its receptors could be increased and related to the development of proliferative synovitis in hemophilia A patients with severe HA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
