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

Autor: Massimo Innocenti, Silvia Linari, Marco Matucci-Cerinic, Christian Carulli, Irene Rosa, Mirko Manetti, Daniela Melchiorre, Eloisa Romano, Giancarlo Castaman, Lidia Ibba-Manneschi
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Journal of Clinical Medicine
Volume 8
Issue 7
Journal of Clinical Medicine, Vol 8, Iss 7, p 939 (2019)
ISSN: 2077-0383
DOI: 10.3390/jcm8070939
Popis: Hemophilic arthropathy (HA) typically begins with proliferative synovitis that shares some similarities with inflammatory arthritides, in which the proinflammatory cytokine tumor necrosis factor (TNF)-&alpha
has a crucial pathogenetic role. Inappropriate release of TNF-&alpha
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-&alpha
and synovial tissue expression of the TNF-&alpha
/TNF receptor (TNF-R) system could be increased and related to joint damage in hemophilia A patients with severe HA. Serum levels of TNF-&alpha
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-&alpha
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-&alpha
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-&alpha
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-&alpha
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-&alpha
did not induce apoptosis either in HA or in osteoarthritis fibroblast-like synoviocytes. The TNF-&alpha
/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-&alpha
therapeutic feasibility in hemophiliacs.
Databáze: OpenAIRE
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