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It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproliferative inflammation in SpA. We observed a marked increase of transmembrane (tm) versus soluble (s) TNF in SpA versus RA together with a decrease in the enzymatic activity of ADAM17. In contrast with the destructive polysynovitis observed in classical TNF overexpression models, mice overexpressing tmTNF developed axial and peripheral joint disease with synovitis, enthesitis, and osteitis. Histological and radiological assessment evidenced marked endochondral new bone formation leading to joint ankylosis over time. SpA-like inflammation, but not osteoproliferation, was dependent on TNF-receptor I and mediated by stromal tmTNF overexpression. Collectively, these data indicate that TNF can drive distinct inflammatory pathologies. We propose that tmTNF is responsible for the key pathological features of SpA.<\/jats:p>","DOI":"10.1084\/jem.20200288","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T02:21:25Z","timestamp":1590546085000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-4760","authenticated-orcid":true,"given":"Merlijn H.","family":"Kaaij","sequence":"first","affiliation":[{"name":"Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 1"},{"name":"Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa N.","family":"van Tok","sequence":"additional","affiliation":[{"name":"Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 1"},{"name":"Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris C.","family":"Blijdorp","sequence":"additional","affiliation":[{"name":"Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 1"},{"name":"Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9253-1241","authenticated-orcid":true,"given":"Carmen A.","family":"Ambarus","sequence":"additional","affiliation":[{"name":"Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 1"},{"name":"Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Stock","sequence":"additional","affiliation":[{"name":"Medizinische Klinik 3 - 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