TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A

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.

Unique inflammatory signature in haemophilic arthropathy: miRNA changes due to interaction between blood and fibroblast‐like synoviocytes

“…Following LPS activation of FLS in RA, non‐expression of TNF‐α has been reported due to epigenetic regulation 17 . Of note is that TNF‐α is likewise key to inflammation in HA, as recently published with regard to the role of the iRhom2/ADAM17/TNF‐α pathway 39 and also as a crucial mediator of proliferative synovitis in haemophilia A 39 …”

A Translational Study of TNF-Alpha Antagonists as an Adjunctive Therapy for Preventing Hemophilic Arthropathy

“…Consequently, TNF antagonists, e.g., etanercept, are clinically efficacious for the treatment of RA as they delay joint destruction via several mechanisms, such as decreasing cell recruitment to the inflamed joint [34,35] and synovial chemotactic cytokine expression [36]. In a recent study, Maneti M et al reported the crucial role of TNF-α/TNF-R system in the pathogenesis of hemophilic athropathy, therefore can be employed as a new attractive target for the prevention and treatment of joint damage in hemophilic arthropathy patients [37], which was proven by the current study.…”

Asymptomatic Joint Bleeding and Joint Health in Hemophilia: A Review of Variables, Methods, and Biomarkers

“…52 In another study, serum levels of the proinflammatory cytokine TNF-α were significantly elevated in patients with hemophilic arthropathy compared to healthy controls (p<0.0001). 84 Moreover, TNF-α levels were positively correlated with the number of joint bleeds, degree of synovial hypertrophy, and clinical and ultrasound joint outcomes. The authors suggest that TNF-α is involved in the progression of hemophilic arthropathy and could be a suitable biomarker to detect joint deterioration in patients with hemophilia.…”

“…The authors suggest that TNF-α is involved in the progression of hemophilic arthropathy and could be a suitable biomarker to detect joint deterioration in patients with hemophilia. 84 However, TNF-α is an acute phase inflammatory marker that is elevated in a range of conditions, including rheumatoid arthritis, and as such is not specific to hemophilic submit your manuscript | www.dovepress.com…”