Plasma osteopontin as a marker for damage in pediatric systemic lupus erythematosus

Abstract

Introduction: Osteopontin (OPN; aka SPP1 and Eta-1) is a secreted phosphoprotein that functions in macrophage and T cell adhesion, migration, and signaling, and plays an important role in tissue and wound repair. OPN has been implicated in IFN-a production, and participates in monocyte/macrophage recruitment to kidneys in SLE, where it may functionally contribute to dysregulated tissue repair and fibrosis associated with chronic inflammation. We investigated the relationship of OPN protein levels and genetic variants with disease manifestations in pediatric SLE (pSLE), a subset with an increased proportion of lupus nephritis compared with SLE of adult onset. Methods: DNA and plasma were collected from 72 (52 female; 20 male) pSLE patients (age of SLE onset < 18 years), and 51 healthy controls (32 female; 19 male) consisting of 35 unaffected siblings and 16 unrelated young people. All subjects were 4) had high IFN activity (p = 0.0009), as in previous research, but disease activity did not correlate with cOPN in this cross-sectional analysis. Overall, cOPN was significantly higher in pSLE versus healthy unrelated controls (p < 0.001) with increasing cOPN correlating with SDI (R = 0.5; p = 0.0003). High IFN activity was more likely in pSLE patients with cOPN levels in the top quartile compared with those in the lowest (p = 0.03); similarly, pSLE patients with an SDI > 0 were more likely to have high IFN activity than those with SDI = 0 (p = 0.02). Considering disease status, 5 OPN variants previously associated with SLE, and gender as covariates in a multivariate regression analysis, the 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) of OPN (rs1126772 and rs9138) were associated with increased cOPN (p = 0.004 and 0.02, respectively). Interestingly, both 3' UTR SNPs as well as a promoter variant, rs2857094, were associated with SDI > 0 (ORs of 1.5-2.2; p < 0.01 for each SNP); we also observed rs2857094 allelic association with increased percentage of glomerulonephritis in pSLE (87% vs. 60%; p < 0.0001). In 3/3 renal biopsies from patients with diffuse proliferative glomerulonephritis, we noted the co-localization of OPN with macrophage marker CD68. Conclusion: Genetic variants regulate OPN levels, which may contribute to the progression of tissue injury in pSLE, possibly by tissue-infiltrating monocytes/macrophages. The potential of OPN as a predictor of global and/or renal damage in pSLE requires further study in a longitudinal cohort.