Role of oncostatin M and its receptor in the inflammatory pathogenesis of graves' orbitopathy.

Abstract

Purpose: Oncostatin M (OSM) and its receptor (OSMR) are implicated in chronic inflammatory diseases. The role of OSM in Graves' orbitopathy (GO) pathogenesis remains unclear. Here, we investigated the role of OSM-OSMR signaling in GO pathogenesis and assessed its potential as a therapeutic target.

Methods: Orbital tissues from GO patients and healthy controls were analyzed for OSM, OSMR, and leukemia inhibitory factor receptor (LIFR) expression levels using quantitative real-time PCR. Cultured orbital fibroblasts were treated with recombinant human OSM (rhOSM) and interleukin (IL)-1β to evaluate changes in inflammatory mediator levels and intracellular signaling pathways. OSMR expression was silenced using small interfering RNA. Western blotting was used to assess cytokine and adipogenic marker levels and pathway activation. Adipogenic differentiation was quantified using Oil Red O staining and spectrophotometry.

Results: GO orbital tissues showed significantly increased OSM, OSMR, and LIFR expression. IL-1β stimulation induced time-dependent upregulation of OSM and OSMR expression in orbital fibroblasts. rhOSM pretreatment enhanced IL-1β-induced IL-6, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and cyclooxygenase-2 expression while selectively suppressing IL-8 expression. OSMR silencing reduced inflammatory mediator expression and decreased phosphorylation of Janus kinase 2 and mitogen-activated protein kinase components (JNK, ERK, and p38). OSMR knockdown impaired adipogenic differentiation and downregulated terminal adipocyte marker levels, including adipocyte protein 2 and adiponectin.

Conclusion: OSM-OSMR signaling amplifies IL-1β-induced inflammatory responses and promotes terminal adipogenic differentiation in GO orbital fibroblasts. This dual regulatory function suggests OSMR as a novel therapeutic target for modulating inflammation and tissue remodeling in GO.