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

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## 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...

## Key facts

- **NIH application ID:** 10579760
- **Project number:** 1I01BX005927-01A1
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Robert A. Terkeltaub
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579760

## Citation

> US National Institutes of Health, RePORTER application 10579760, Intersections of matrix biology with inflammation in a new model of gout (1I01BX005927-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10579760. Licensed CC0.

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