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Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia\u2010independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)\/EULAR gout classification criteria (the proband).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted whole\u2010genome sequencing, quantitative proteomics, whole\u2010blood RNA\u2010sequencing analysis using serum samples from the proband. We used a mouse model of IL\u20101\u03b2\u2013induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lubricin level was attenuated in human proband serum and associated with elevated acute\u2010phase reactants and inflammatory whole\u2010blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of <jats:italic>NLRP3<\/jats:italic> and of inter\u2010\u03b1 trypsin inhibitor heavy chain 3, an inhibitor of lubricin\u2010degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll\u2010like receptor 2 (TLR\u20102) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). Lubricin blunted urate crystal precipitation and IL\u20101\u03b2 induction of xanthine oxidase and urate in cultured macrophages (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). In lubricin\u2010deficient mice, injection of IL\u20101\u03b2 in knees increased xanthine oxidase\u2013positive synovial resident M1 macrophages (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious <jats:italic>NLRP3<\/jats:italic> variants. Lubricin suppressed monosodium urate crystallization and blunted IL\u20101\u03b2\u2013induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR\u20102 signaling.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42413-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42413","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T05:14:24Z","timestamp":1669958064000},"page":"794-805","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8925-4255","authenticated-orcid":false,"given":"Khaled","family":"Elsaid","sequence":"first","affiliation":[{"name":"Chapman University School of Pharmacy  Irvine California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0844-8726","authenticated-orcid":false,"given":"Tony R.","family":"Merriman","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, and Department of Biochemistry University of Otago  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leigh\u2010Ana","family":"Rossitto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences  UC San Diego California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9611-8163","authenticated-orcid":false,"given":"Ru","family":"Liu\u2010Bryan","sequence":"additional","affiliation":[{"name":"VA San Diego Healthcare System, San Diego, and Department of Medicine  UC San Diego, La Jolla California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"Karsh","sequence":"additional","affiliation":[{"name":"The Ottawa Hospital, Division of Rheumatology University of Ottawa  Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Phipps\u2010Green","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Otago  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory D.","family":"Jay","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Alpert School of Medicine, and Division of Biomedical 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