Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia

Abstract

In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1β (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 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).Methods. We conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1β-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.Results. Lubricin level was attenuated in human proband serum and 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-α trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading 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-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (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, injection of IL-1β in knees increased xanthine oxidase-positive synovial resident M1 macrophages (P < 0.05).Conclusion. Our findings 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 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-2 signaling.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators

“…We detected decrease in serum of the phagocyte-recruiting chemokine PPBP/CXCL7 37 , and decreased lactoferrin, a neutrophil-released coactivator of the lubricin-degrading serine protease Cathepsin G 38 . That nding was of note, since Cathepsin G is a major degrader of lubricin, which functions as a substantial constitutive suppressor of gouty in ammation and urate production by synovial resident macrophages 39 . We also observed an increase in monocyte/macrophage-expressed keratin-related proteins (KRT9,14,16), further validated by Cohort 1 gout patient PBMC proteomics.…”

Novel genetic loci in adolescent-onset gout derived from whole genome sequencing of a Chinese cohort

“…That process involves the joint surface lubrication by lubricin, collagen II release from cartilage, and homeostasis of articular cartilage, synovium, and other tissues in the joint, which is disrupted by several proteases released by inflammatory cells. 33 Moreover, there are 16419 target genes of the RCOR1 transcription factor repressor in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset (http://www.ncbi.nlm.nih.gov/gene/23186). They include not only NLRP3, L-1β and IL-6, but also multiple genes that regulate lubricin proteolytic turnover (ITIH3, THBS1, ELANE, TLR2, SERPINB6).…”

“…They include not only NLRP3, L-1β and IL-6, but also multiple genes that regulate lubricin proteolytic turnover (ITIH3, THBS1, ELANE, TLR2, SERPINB6). 33 Notably, RCOR1 also modulates articular chondrocyte homeostasis and cartilage integrity. 34 This is the first report of comprehensive characterization of adolescent-onset gout genomes, and risk loci of early-onset gout were identified.…”

Triazole derivatives as potential xanthine oxidase inhibitors: Design, enzyme inhibition potential, and docking studies

“…[ 4 ] It is characterized by the sedimentation and crystallization of UA crystals in joints and its adjoining tissues thus defining most prevalent case of inflammatory arthritis. [ 5 ] Tophi deposits of monosodium urate crystals and nephrolithiasis are some of its clinical manifestations. [ 6 ] Moreover, gout can further aggravate renal and cardiovascular disorders.…”