{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:14:22Z","timestamp":1790100862336,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T00:00:00Z","timestamp":1561680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Hemophilic arthropathy (HA) typically begins with proliferative synovitis that shares some similarities with inflammatory arthritides, in which the proinflammatory cytokine tumor necrosis factor (TNF)-\u03b1 has a crucial pathogenetic role. Inappropriate release of TNF-\u03b1 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-\u03b1 and synovial tissue expression of the TNF-\u03b1\/TNF receptor (TNF-R) system could be increased and related to joint damage in hemophilia A patients with severe HA. Serum levels of TNF-\u03b1 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-\u03b1 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-\u03b1, 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-\u03b1, 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-\u03b1 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-\u03b1 did not induce apoptosis either in HA or in osteoarthritis fibroblast-like synoviocytes. The TNF-\u03b1\/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-\u03b1 therapeutic feasibility in hemophiliacs.<\/jats:p>","DOI":"10.3390\/jcm8070939","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T11:20:26Z","timestamp":1561720826000},"page":"939","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["TNF-\u03b1\/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-8480","authenticated-orcid":false,"given":"Mirko","family":"Manetti","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Linari","sequence":"additional","affiliation":[{"name":"Center for Bleeding Disorders, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2744-8625","authenticated-orcid":false,"given":"Eloisa","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Rheumatology, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6352-0175","authenticated-orcid":false,"given":"Irene","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0845-7940","authenticated-orcid":false,"given":"Christian","family":"Carulli","sequence":"additional","affiliation":[{"name":"First Orthopedic Clinic, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Innocenti","sequence":"additional","affiliation":[{"name":"First Orthopedic Clinic, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Matucci-Cerinic","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Rheumatology, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Ibba-Manneschi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Castaman","sequence":"additional","affiliation":[{"name":"Center for Bleeding Disorders, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Melchiorre","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Rheumatology, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0140-6736(15)01123-X","article-title":"The past and future of haemophilia: Diagnosis, treatments, and its complications","volume":"388","author":"Peyvandi","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/hae.13236","article-title":"Differential effects of bleeds on the development of arthropathy-basic and applied issues","volume":"23","author":"Mastbergen","year":"2017","journal-title":"Haemophilia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1111\/j.1538-7836.2010.03962.x","article-title":"Blood-induced joint disease: The pathophysiology of hemophilic arthropathy","volume":"8","author":"Valentino","year":"2010","journal-title":"J. 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