GPSM3 as a Therapeutic Target for Rheumatoid Arthritis

Abstract

ABSTRACT: Rheumatoid arthritis (RA) is mediated by dysregulation of immune‐system cells. G Protein Signaling Modulator‐3 (GPSM3) is a GoLoco motif protein with an expression profile restricted to leukocytes and the greatest expression seen in monocytes and neutrophils ‐‐ two immune‐system cell lineages paramount to RA pathogenesis. In a collagen autoantibody‐induced model of arthritis, we showed that GPSM3 deficiency protects mice against inflammatory sequelae. GPSM3‐deficient monocytes exhibit disrupted chemotaxis ex vivo, suggesting a role for GPSM3 in cell migration during acute inflammatory arthritis. Notably, human polymorphisms in GPSM3 are associated with a decreased likelihood of developing RA. Given these data, we speculate that the GPSM3 SNPs result in decreased GPSM3 expression/function. To test this hypothesis, we genotyped 50 healthy volunteers, from whom we obtained buccal swabs and whole blood specimens. The SNP minor allele frequency in these volunteers was 0.3 (n = 50). qRT‐PCR analyses of whole blood‐isolated RNA from volunteers heterozygous for the GPSM3 SNPs showed a 32% decrease (p < 0.05) in GPSM3 transcript abundance compared to volunteers without the minor SNP allele (n = 5), suggesting that the minor allele associates with a decrease in GPSM3 expression. From these data, we conclude that GPSM3 SNPs could result in decreased transcript abundance in vivo, which may mimic the ‘protective’ phenotype observed in GPSM3‐deficient mice. Similar studies are underway with RA patients and demographically matched volunteers to examine whether GPSM3 SNP genotype affects (1) transcript levels, (2) protein immunoreactivity, and (3) disease severity in RA patients.