Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis
TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproli...
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| Veröffentlicht in: | The Journal of experimental medicine 2020-10, Vol.217 (10) |
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| creator | Kaaij, Merlijn H van Tok, Melissa N Blijdorp, Iris C Ambarus, Carmen A Stock, Michael Pots, Désiree Knaup, Véronique L Armaka, Marietta Christodoulou-Vafeiadou, Eleni van Melsen, Tessa K Masdar, Huriatul Eskes, Harry J P P Yeremenko, Nataliya G Kollias, George Schett, Georg Tas, Sander W van Duivenvoorde, Leonie M Baeten, Dominique L P |
| description | TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). 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. |
| doi_str_mv | 10.1084/jem.20200288 |
| format | Article |
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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.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20200288</identifier><identifier>PMID: 32662821</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>ADAM17 Protein - metabolism ; Adult ; Animals ; Arthritis - etiology ; Arthritis - metabolism ; Disease Models, Animal ; Female ; Fluorescent Antibody Technique ; Humans ; Innate Immunity and Inflammation ; Joints - metabolism ; Male ; Mice ; Osteogenesis ; Receptors, Tumor Necrosis Factor - metabolism ; Spondylarthritis - etiology ; Spondylarthritis - metabolism ; Synovitis - etiology ; Synovitis - metabolism ; Tumor Necrosis Factor-alpha - metabolism ; Tumor Necrosis Factor-alpha - physiology</subject><ispartof>The Journal of experimental medicine, 2020-10, Vol.217 (10)</ispartof><rights>2020 Kaaij et al.</rights><rights>2020 Kaaij et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-71ccdff0c79c03d5c13a5aff30989598154c516b02a999aa178a433b2473d82f3</citedby><cites>FETCH-LOGICAL-c427t-71ccdff0c79c03d5c13a5aff30989598154c516b02a999aa178a433b2473d82f3</cites><orcidid>0000-0003-0985-9076 ; 0000-0002-9253-1241 ; 0000-0001-5671-9143 ; 0000-0002-4554-4760 ; 0000-0002-0121-5543 ; 0000-0003-1867-3150 ; 0000-0002-0951-4716 ; 0000-0001-8740-9615</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32662821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaaij, Merlijn H</creatorcontrib><creatorcontrib>van Tok, Melissa N</creatorcontrib><creatorcontrib>Blijdorp, Iris C</creatorcontrib><creatorcontrib>Ambarus, Carmen A</creatorcontrib><creatorcontrib>Stock, Michael</creatorcontrib><creatorcontrib>Pots, Désiree</creatorcontrib><creatorcontrib>Knaup, Véronique L</creatorcontrib><creatorcontrib>Armaka, Marietta</creatorcontrib><creatorcontrib>Christodoulou-Vafeiadou, Eleni</creatorcontrib><creatorcontrib>van Melsen, Tessa K</creatorcontrib><creatorcontrib>Masdar, Huriatul</creatorcontrib><creatorcontrib>Eskes, Harry J P P</creatorcontrib><creatorcontrib>Yeremenko, Nataliya G</creatorcontrib><creatorcontrib>Kollias, George</creatorcontrib><creatorcontrib>Schett, Georg</creatorcontrib><creatorcontrib>Tas, Sander W</creatorcontrib><creatorcontrib>van Duivenvoorde, Leonie M</creatorcontrib><creatorcontrib>Baeten, Dominique L P</creatorcontrib><title>Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). 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.</description><subject>ADAM17 Protein - metabolism</subject><subject>Adult</subject><subject>Animals</subject><subject>Arthritis - etiology</subject><subject>Arthritis - metabolism</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Fluorescent Antibody Technique</subject><subject>Humans</subject><subject>Innate Immunity and Inflammation</subject><subject>Joints - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Osteogenesis</subject><subject>Receptors, Tumor Necrosis Factor - metabolism</subject><subject>Spondylarthritis - etiology</subject><subject>Spondylarthritis - metabolism</subject><subject>Synovitis - etiology</subject><subject>Synovitis - metabolism</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor Necrosis Factor-alpha - physiology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LAzEUDKLY-nHzLHv04NaXj22SiyDFLxC91HNIs4lN2Wxqsi34703xAz0NzBvmzXuD0BmGCQbBrlY2TAgQACLEHhrjhkEtGyr20bhwpMYAfISOcl4BYMaa6SEaUTKdEkHwGNl50n0ONiwK2mr-fFe1yW9trmIebFyn2Hlnkx4KV62i74fK967TIRQq9lWywfc-G1sG0VXLTdB9ldexbz-6qNOwTH7w-QQdON1le_qNx-j17nY-e6ifXu4fZzdPtWGEDzXHxrTOgeHSAG0bg6lutHMUpJCNFOU20-DpAoiWUmqNudCM0gVhnLaCOHqMrr9815tFsO0uVdKdWicfdPpQUXv1f9L7pXqLW8UbyhmQYnDxbZDi-8bmQYXdcV1XnhM3WRFGKJcCsCjSyy-pSTHnZN3vGgxq14wqzaifZor8_G-0X_FPFfQTOH2NJw</recordid><startdate>20201005</startdate><enddate>20201005</enddate><creator>Kaaij, Merlijn H</creator><creator>van Tok, Melissa N</creator><creator>Blijdorp, Iris C</creator><creator>Ambarus, Carmen A</creator><creator>Stock, Michael</creator><creator>Pots, Désiree</creator><creator>Knaup, Véronique L</creator><creator>Armaka, Marietta</creator><creator>Christodoulou-Vafeiadou, Eleni</creator><creator>van Melsen, Tessa K</creator><creator>Masdar, Huriatul</creator><creator>Eskes, Harry J P P</creator><creator>Yeremenko, Nataliya G</creator><creator>Kollias, George</creator><creator>Schett, Georg</creator><creator>Tas, Sander W</creator><creator>van Duivenvoorde, Leonie M</creator><creator>Baeten, Dominique L P</creator><general>Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0985-9076</orcidid><orcidid>https://orcid.org/0000-0002-9253-1241</orcidid><orcidid>https://orcid.org/0000-0001-5671-9143</orcidid><orcidid>https://orcid.org/0000-0002-4554-4760</orcidid><orcidid>https://orcid.org/0000-0002-0121-5543</orcidid><orcidid>https://orcid.org/0000-0003-1867-3150</orcidid><orcidid>https://orcid.org/0000-0002-0951-4716</orcidid><orcidid>https://orcid.org/0000-0001-8740-9615</orcidid></search><sort><creationdate>20201005</creationdate><title>Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis</title><author>Kaaij, Merlijn H ; 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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. 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| subjects | ADAM17 Protein - metabolism Adult Animals Arthritis - etiology Arthritis - metabolism Disease Models, Animal Female Fluorescent Antibody Technique Humans Innate Immunity and Inflammation Joints - metabolism Male Mice Osteogenesis Receptors, Tumor Necrosis Factor - metabolism Spondylarthritis - etiology Spondylarthritis - metabolism Synovitis - etiology Synovitis - metabolism Tumor Necrosis Factor-alpha - metabolism Tumor Necrosis Factor-alpha - physiology |
| title | Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis |
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