{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:16:21Z","timestamp":1791317781062,"version":"4.3.1"},"reference-count":12,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["ZIAAR041199"],"award-info":[{"award-number":["ZIAAR041199"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K19593"],"award-info":[{"award-number":["25K19593"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Carbamylation, a nonenzymatic post\u2010translational modification, contributes to rheumatoid arthritis (RA) pathogenesis. Anti\u2010carbamylated protein antibodies (anti\u2010CarP) occur in\u2009around\u200950% of patients with RA and associate with greater joint damage. Neutrophil extracellular traps (NETs) are a major source of carbamylated autoantigens. We sought to study how carbamylation and anti\u2010CarP antibodies promote joint pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>NETs were generated with calcium ionophore and analyzed for carbamylation by immunofluorescence, flow cytometry, and mass spectrometry. Enzymatic pathways were interrogated using pharmacologic inhibitors and peptidyl arginine deiminase (PAD)2\/4 deficient mice. Degradation kinetics of carbamylated histone H3 (carH3) were evaluated with neutrophil elastase (NE) and anti\u2010CarP IgG from patients with RA. Toll\u2010like receptor 4 (TLR4) activation was quantified using a HEK293 reporter line. RA fibroblast\u2010like synoviocytes (FLS) were stimulated with carH3 or carH3\u2010IgG immune complexes (ICs) and profiled by RNA\u2010sequencing and enzyme\u2010linked immunosorbent assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Histone carbamylation, especially of H3, occurred during NETosis and was independent of peptidylarginine deiminase\u20104, myeloperoxidase, NE, or oxidative pathways. CarH3 was rapidly degraded by NE, but anti\u2010CarP antibodies protected it from proteolysis. NETs exposed to anti\u2010CarP IgG triggered stronger TLR4 activation and enhanced osteoclastogenesis. In FLS, carH3 and particularly carH3\u2010ICs induced robust up\u2010regulation of pro\u2010inflammatory genes and cytokine secretion (interleukin [IL\u2010]6, IL\u20108, MCP\u20101, GM\u2010CSF). Transcriptomic analysis revealed enrichment of immune activation, chemotaxis, and angiogenesis pathways, most pronounced with carH3\u2010IC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Anti\u2010CarP antibodies stabilize carH3 within NETs, amplifying its pro\u2010inflammatory and osteoclastogenic activity. The resulting carH3\u2010IgG ICs potently activate FLS, linking humoral immunity to tissue inflammation and bone destruction in RA. These findings identify carH3 stabilization as a potential therapeutic target in antibody\u2010mediated joint damage.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70158-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70158","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T10:14:37Z","timestamp":1775211277000},"page":"2074-2081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Anti\u2010Carbamylated Protein Antibodies Stabilize Carbamylated Histone\n                    <scp>H3<\/scp>\n                    to Promote Synovial Activation and Neutrophil Extracellular Trap\u2010Mediated Bone Loss in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9250-1851","authenticated-orcid":false,"given":"Shuichiro","family":"Nakabo","sequence":"first","affiliation":[{"name":"Systemic Autoimmunity Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Hanata","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Patino\u2010Martinez","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Holewinski","sequence":"additional","affiliation":[{"name":"Frederick National Laboratory for Cancer Research National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Barrera\u2010Vargas","sequence":"additional","affiliation":[{"name":"Department of Medical Education Instituto Nacional de Ciencias M\u00e9dicas y de la Nutrici\u00f3n  Salvador Zubir\u00e1n Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Merayo\u2010Chalico","sequence":"additional","affiliation":[{"name":"Department of Immunology and Rheumatology Instituto Nacional de Ciencias M\u00e9dicas y de la Nutrici\u00f3n  Salvador Zubir\u00e1n Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Coonrod","sequence":"additional","affiliation":[{"name":"Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University  Ithaca New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0230-6607","authenticated-orcid":false,"given":"David A.","family":"Fox","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan  Ann Arbor Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana J.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-1464","authenticated-orcid":false,"given":"Carmelo","family":"Carmona\u2010Rivera","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health  Bethesda 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