Suppression of renal crystal formation, inflammation, and fibrosis by blocking oncostatin M receptor β signaling

Abstract

Oncostatin M (OSM) has pleiotropic effects on various inflammatory diseases, including kidney stone disease. The prevalence of kidney stones has increased worldwide, despite recent therapeutic advances, due to its high recurrence rate, suggesting the importance of prevention of repeated recurrence in the treatment of kidney stone disease. Using a mouse model of renal crystal formation, we investigated the preventive effects of blockade of OSM receptor β (OSMRβ) signaling on the development of kidney stone disease by treatment with a monoclonal anti-OSMRβ antibody that we generated. The anti-OSMRβ antibody abrogated OSM-induced phosphorylation of STAT3 and expression of crystal-binding molecules (Opn, Anxa1, Anxa2) and inflammation/fibrosis-associated molecules (Tnfa, Tgfb, Col1a2) in renal tubular epithelial cells and fibroblasts. In glyoxylate-injected mice, a mouse model of renal crystal formation, there was significant suppression of crystal deposits and expression of crystal-binding molecules (Opn, Anxa1, Anxa2), a tubular injury marker (Kim-1), and inflammation/fibrosis-associated molecules (Tnfa, Il1b, Mcp-1, Tgfb, Col1a2) in the kidneys of the anti-OSMRβ antibody-treated mice, compared with those in vehicle- or isotype control antibody-treated mice. In addition, treatment with the anti-OSMRβ antibody significantly decreased infiltrating macrophages and fibrosis in the kidneys. These findings suggest that anti-OSMRβ antibody-treatment may be effective in preventing kidney stone disease.