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Article

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

1
Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy
2
Center for Bleeding Disorders, Careggi University Hospital, 50134 Florence, Italy
3
Department of Experimental and Clinical Medicine, Section of Rheumatology, University of Florence, 50134 Florence, Italy
4
First Orthopedic Clinic, Careggi University Hospital, 50134 Florence, Italy
*
Authors to whom correspondence should be addressed.
G.C. and D.M. contributed equally to this work.
J. Clin. Med. 2019, 8(7), 939; https://doi.org/10.3390/jcm8070939
Received: 7 May 2019 / Revised: 17 June 2019 / Accepted: 26 June 2019 / Published: 28 June 2019
(This article belongs to the Section Hematology)
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. View Full-Text
Keywords: hemophilic arthropathy; TNF-α; TNF receptors; fibroblast-like synoviocytes; proliferative synovitis hemophilic arthropathy; TNF-α; TNF receptors; fibroblast-like synoviocytes; proliferative synovitis
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MDPI and ACS Style

Manetti, M.; Linari, S.; Romano, E.; Rosa, I.; Carulli, C.; Innocenti, M.; Matucci-Cerinic, M.; Ibba-Manneschi, L.; Castaman, G.; Melchiorre, D. TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A. J. Clin. Med. 2019, 8, 939. https://doi.org/10.3390/jcm8070939

AMA Style

Manetti M, Linari S, Romano E, Rosa I, Carulli C, Innocenti M, Matucci-Cerinic M, Ibba-Manneschi L, Castaman G, Melchiorre D. TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A. Journal of Clinical Medicine. 2019; 8(7):939. https://doi.org/10.3390/jcm8070939

Chicago/Turabian Style

Manetti, Mirko, Silvia Linari, Eloisa Romano, Irene Rosa, Christian Carulli, Massimo Innocenti, Marco Matucci-Cerinic, Lidia Ibba-Manneschi, Giancarlo Castaman, and Daniela Melchiorre. 2019. "TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A" Journal of Clinical Medicine 8, no. 7: 939. https://doi.org/10.3390/jcm8070939

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