{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T23:42:03Z","timestamp":1793403723405,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010414","name":"Health Research Board","doi-asserted-by":"publisher","award":["ILP\u2010POR\u20102022\u2010014"],"award-info":[{"award-number":["ILP\u2010POR\u20102022\u2010014"]}],"id":[{"id":"10.13039\/100010414","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Both susceptibility to, and severity of, rheumatoid arthritis (RA) is associated with the rs26232 C allele. Our primary aim was to identify the biologic mechanism underlying this association.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Expression of surrounding genes was compared among rs26232 genotypes. Publicly available databases were used to correlate expression with RA inflammation and single\u2010cell synovial distribution. Inhibition of gene expression and activity was achieved using small interfering RNA and a pharmacology agent and effects on RA synovial fibroblasts (RASFs) characteristics in vitro were assayed. The amidated secretome of synovial fibroblasts were characterized by mass spectrometry and enzyme\u2010linked immunosorbent assay. Effects of amidated peptides on macrophage polarity were determined using an RASF\u2013macrophage coculture module.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      rs26232 C is associated with low expression of peptidylglycine alpha\u2010amidating monooxygenase (\n                      <jats:italic>PAM<\/jats:italic>\n                      ) in multiple tissues including RASFs. Synovial\n                      <jats:italic>PAM<\/jats:italic>\n                      is highly expressed in RASFs but not immune cells, and levels are inversely correlated with synovial and systemic levels of inflammation. Inhibition of\n                      <jats:italic>PAM<\/jats:italic>\n                      in RASFs increased tissue\u2010damaging activities such as invasiveness in vitro. The most abundant amidated peptides secreted by RASFs were adrenomedullin (ADM) and pro\u2010ADM N\u2010terminal peptide (PAMP). Incubation of RASFs with either peptide inhibited interleukin\u20106 (IL\u20106) and IL\u20108, increased transforming growth factor \u03b2 production, and reduced invasiveness in vitro. Inhibition of amidation in an RASF\u2013macrophage coculture model skewed the macrophages to proinflammatory MerTK\n                      <jats:sup>\u2212<\/jats:sup>\n                      phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Genetically determined low\n                      <jats:italic>PAM<\/jats:italic>\n                      reduces the anti\u2010inflammatory and tissue\u2010damaging activities of ADM and PAMP mediated by macrophages and RASFs, explaining the association of rs26232 C with RA severity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70123","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T06:01:02Z","timestamp":1773036062000},"page":"1837-1849","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tissue Damage in Rheumatoid Arthritis Is Genetically Linked to Low Peptidylglycine Alpha\u2010Amidating Monooxygenase Activity in Synovial Fibroblasts"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1061-073X","authenticated-orcid":false,"given":"Kevin J.","family":"Sheridan","sequence":"first","affiliation":[{"name":"University College Dublin Centre for Arthritis Research, Conway Institute, University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2014-934X","authenticated-orcid":false,"given":"Emma 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