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

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 arthro...

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Autores principales: Manetti, Mirko, Linari, Silvia, Romano, Eloisa, Rosa, Irene, Carulli, Christian, Innocenti, Massimo, Matucci-Cerinic, Marco, Ibba-Manneschi, Lidia, Castaman, Giancarlo, Melchiorre, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678637/
https://www.ncbi.nlm.nih.gov/pubmed/31261789
http://dx.doi.org/10.3390/jcm8070939
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author Manetti, Mirko
Linari, Silvia
Romano, Eloisa
Rosa, Irene
Carulli, Christian
Innocenti, Massimo
Matucci-Cerinic, Marco
Ibba-Manneschi, Lidia
Castaman, Giancarlo
Melchiorre, Daniela
author_facet Manetti, Mirko
Linari, Silvia
Romano, Eloisa
Rosa, Irene
Carulli, Christian
Innocenti, Massimo
Matucci-Cerinic, Marco
Ibba-Manneschi, Lidia
Castaman, Giancarlo
Melchiorre, Daniela
author_sort Manetti, Mirko
collection PubMed
description 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.
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spelling pubmed-66786372019-08-19 TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A Manetti, Mirko Linari, Silvia Romano, Eloisa Rosa, Irene Carulli, Christian Innocenti, Massimo Matucci-Cerinic, Marco Ibba-Manneschi, Lidia Castaman, Giancarlo Melchiorre, Daniela J Clin Med Article 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. MDPI 2019-06-28 /pmc/articles/PMC6678637/ /pubmed/31261789 http://dx.doi.org/10.3390/jcm8070939 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Manetti, Mirko
Linari, Silvia
Romano, Eloisa
Rosa, Irene
Carulli, Christian
Innocenti, Massimo
Matucci-Cerinic, Marco
Ibba-Manneschi, Lidia
Castaman, Giancarlo
Melchiorre, Daniela
TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A
title TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A
title_full TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A
title_fullStr TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A
title_full_unstemmed TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A
title_short TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A
title_sort tnf-α/tnf-r system may represent a crucial mediator of proliferative synovitis in hemophilia a
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678637/
https://www.ncbi.nlm.nih.gov/pubmed/31261789
http://dx.doi.org/10.3390/jcm8070939
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