Gout is a highly prevalent disease manifesting most commonly as acute, episodic synovitis that characteristically is excruciatingly painful. Gout continues to grow as a public health problem. The disorder is promoted by elevated body stores of uric acid, and the clinical phenotypes of arthritis are caused by inflammatory responses associated with articular deposits of urate crystals. However, gout develops in only a minority subset of hyperuricemic subjects. Moreover, clinical responses to deposited urate crystals are highly variable, including the frequency and extent of acute arthritis, and progression to palpable subcutaneous tophi, chronic arthritis, and erosive joint damage. There is unmet need to define new therapy targets and biomarkers for incident gout and progression to erosive joint disease. The rationale for this high risk/high reward application is that by clarifying major gaps in knowledge in these areas, the work will be paradigm-shifting, and potentially identify new targets to help prevent and limit gout-associated morbidity. Emerging findings, including from certain arthropathies other than gout, suggest that altered extracellular matrix O-linked glycoprotein components such as the mucin-type boundary lubricant lubricin, and active urate pumping into the joint by an unidentified transport mechanism play a role in development of gout. Our scientific premise is that, in synovial fibroblast lining cells (FLS), mechanistically linked alterations in lubricin and other mucin-type extracellular matrix O-glycoproteins and increased urate secretion are in a mechanistic lop that promotes ?common gout?, and progression to chronic, destructive synovitis. We will use primarily a combined candidate gene and reverse genetics approach to analyze a highly unusual observation, specifically a case of gout as an ?experiment of nature?. The proband, an otherwise healthy female without hyperuricemia, at age 22 had onset of destructive hip synovitis, and asymmetric acute gouty arthritis flares of small and intermediate joints with classic toe joint gout erosions, and gout definitively confirmed. Collective preliminary data for proband whole genomic DNA, and serum glycomics, proteomics, and glycoproteomics suggest dysregulation in biosynthesis of lubricin and other mucin-type O-glycoproteins that normally serve as constitutive inhibitors of inflammation. Gene candidates are highly enriched in the ?reactome? of TMEM171, an incompletely characterized transmembrane molecule implicated in urate transport and recently defined as a gout susceptibility gene. Specifically, the TMEM171 reactome comprises over 20 molecules involved in glycoprotein biosynthesis, more than 10 mucintype. O-glycoproteins, and over 20 ADAMTS protease superfamily members. The work aims to illuminate novel intersections between synovial extracellular matrix biology, urate metabolism and transport, tophus formation, and synovitis. Positive impact includes building a new disease paradigm for ?common gout?, potential new biomarkers, and possible gout therapeutics from the novel class of O-glycoprotein agents.
Gout is a metabolic disorder, built on excess body stores of uric acid and elevated serum urate, tissue urate crystal deposits, and acute and chronic joint disease linked to induction by urate crystals of IL-1? release and other inflammation pathways. This application builds on novel genomic, glycoproteomic, and glycomic analyses of a unique observation of incident gout, and subsequent aggressive acute and chronic synovitis in an otherwise healthy 22 year old female with normal serum urate. The work will generate a new gout disease paradigm to illuminate previously unseen bridges between urate metabolism within the joint, synovial and extracellular matrix biology, tissue urate crystal deposition and tophus formation, and potentially the wider genomics of common gout.
