Intersections of matrix biology with inflammation in a new model of gout

Va San Diego Healthcare System, San Diego CA

Investigators

Linked publications, trials & patents

Abstract

Hyperuricemia is fundamental in promoting the formation and accumulation of tissue deposits of monosodium urate crystals in gout, a high prevalence disease in Veterans. Urate crystals deposited in the joint promote acute, episodic flares of painful and incapacitating inflammatory arthritis by multiple pathways. Most importantly, urate crystals induce monocyte and macrophage NLRP3 inflammasome-mediated IL-1b release, and phagocyte influx and activation. Chronic inflammation lies beneath acute gout flares, including formation of articular tophi, which cause persistent synovitis and pannus-like erosive joint disease. However, several key aspects of gout pathogenesis remain unclear. In this light, asymptomatic hyperuricemia is over 5 times as prevalent than gout, and synovial fluid urate is enriched relative to serum urate in gout. Thus, passive filtering into the joint of excess circulating urate cannot be the only factor promoting tissue urate crystal deposition and symptomatic arthritis in gout. Furthermore, beyond high body urate burden, native factors that limit only ~15% of gout patients to develop palpable tophi in “tophaceous gout” are unclear. Better understanding factors that limit tophaceous gout, and their biomarkers, is vital due to association with erosive joint damage. To study novel gout prevention and therapy targets, we propose to test a paradigm-shifting core hypothesis for a gout regulation via intersection of inflammation with altered homeostasis of the extracellular matrix O-glycoprotein boundary lubricant lubricin. We specifically posit that the major gouty arthritis NLRP3/IL- 1b driver intersects with the homeostasis of lubricin to increase articular urate crystal deposition, inflammation, and disease progression in gout. Lubricin is an established, constitutive suppressor of experimental gouty inflammation. We observe that IL-1b induces xanthine oxidase and uric acid generation by macrophages, an effect blocked by exogenous lubricin. We find that lubricin markedly suppresses urate crystal formation in vitro. We also have characterized a remarkable “experiment of nature” in a 22 year old female female without hyperuricemia, who developed rapidly progressive crystal-proven gout, with classic and frequent acute flares, and erosive, destructive arthritis, affecting the feet, wrist, and hip. The proband had a heritable NLRP3 gain of function variant, an inflammatory profile of serum biomarkers and the whole blood transcriptome, attenuated serum levels of lubricin, and collective evidence consistent with altered lubricin homeostasis. Our model is that paucity of lubricin in “common gout”, due to heterogeneous mechanisms, enhances articular uric acid and increases the capacity of monosodium urate crystals to form in the joint. We thereby posit that articular lubricin deficiency, suppressible by injectable lubricin supplementation, promotes more severe acute and chronic gouty phenotypes in vivo. Translationally impactful studies will test our model by moving from in vitro to mouse to human studies. In doing so, we will test and compare mucin, and N- and C-terminal domain requirements for lubricin to limit urate crystal formation and macrophage xanthine oxidase activity, and to suppress selected gout pro-inflammatory mechanisms in macrophages. We will test the specific hypothesis that lubricin deficiency promotes ineffective resolution of IL-1b and urate crystal-induced acute articular inflammatory responses. Last, in a large, cross-sectional analysis of sera, we will test for relationships of more frequent gouty arthritis flares and tophaceous gout with low serum levels of lubricin, and certain entirely novel serum biomarkers of lubricin homeostasis pertinent to gout, including lubricin-degrading Cathepsin G activity, the Cathepsin G co-activator Lactoferrin, two inhibitors (Thrombospondin1 (TSP1/THBS1) and SERPINB6) of lubricin-degrading proteases, and the Cathepsin G substrate APP (Amyloid Precursor Protein). Completion of this work is projected to elucidate novel serum biomarkers to help guide gout treatment strategy and intensity, and new therapy targets to limit urate crystal deposition, acute and chronic synovitis, and joint damage in the disease.