Document Type
Article
Publication Date
12-1-2022
Abstract
Objective
In gout, hyperuricemia promotes urate crystal deposition that stimulates the NLRP3 inflammasome and IL-1β-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis meeting ACR/EULAR gout classification criteria in a normouricemic young adult female.
Methods
Whole genome sequencing, quantitative proteomics, whole blood RNA-seq, and IL-1β-induced murine knee synovitis characterized proband candidate genes, biomarkers, and pathogenic mechanisms.
Results
Lubricin was attenuated in proband serum, associated with elevated acute phase reactants and inflammatory whole blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of Inter-Alpha-Trypsin Inhibitor Heavy Chain 3, an inhibitor of lubricin-degrading Cathepsin G. Proband serum protein interactome network changes supported enhanced lubricin degradation, with Cathepsin G activity increased relative to its inhibitors SERPINB6 and Thrombospondin1. TLR2 activation suppressed cultured human synovial fibroblast lubricin mRNA and release (p<0.01). Lubricin blunted urate crystal precipitation, and IL-1β induction of xanthine oxidase and urate in cultured macrophages (p<0.001). In lubricin-deficient mice, IL-1β knee injection increased xanthine oxidase positive synovial resident M1 macrophages (p<0.05).
Conclusion
We linked normouricemic erosive gout to attenuated lubricin, with impaired control of Cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization, and blunted IL-1β-induced increases in macrophage xanthine oxidase and urate. 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 TLR2 signaling.
Recommended Citation
Elsaid K, Merriman TR, Rossitto LA, et al. Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia. Arthritis Rheumatol. 2022. https://doi.org/10.1002/art.42413
Copyright
Wiley
Comments
This is the accepted version of the following article:
Elsaid K, Merriman TR, Rossitto LA, et al. Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia. Arthritis Rheumatol. 2022. https://doi.org/10.1002/art.42413
which has been published in final form at https://doi.org/10.1002/art.42413. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.