TMEM2 inhibits the development of Graves' orbitopathy through the JAK-STAT signaling pathway.

Hong Li, Jie Min, Yucheng Yang, Wendong Suo, Wei Wang, Jiahe Tian, Yujie Qin

The Journal of biological chemistry 2024 Feb

filter terms:

A mouse model was used to investigate the role of the hyaluronidase, transmembrane protein 2 (TMEM2), on the progression of Graves' orbital (GO) disease. We established a GO mouse model through immunization with a plasmid expressing the thyroid stimulating hormone receptor. Orbital fibroblasts (OFs) were subsequently isolated from both GO and non-GO mice for comprehensive in vitro analyses. The expression of TMEM2 was assessed using qRT-PCR, Western blot and immunohistochemistry in vivo. Disease pathology was evaluated by H&E staining and Masson's trichrome staining in GO mouse tissues. Our investigation revealed a notable reduction in TMEM2 expression in GO mouse orbital tissues. Through overexpression and knockdown assays, we demonstrated that TMEM2 suppresses inflammatory cytokines and reactive oxygen species production. TMEM2 also inhibits the formation of lipid droplets in OFs and the expression of adipogenic factors. Further incorporating Gene Set Enrichment Analysis of relevant GEO datasets and subsequent in vitro cell experiments, robustly confirmed that TMEM2 overexpression was associated with a pronounced upregulation of the JAK/STAT signaling pathway. In vivo, TMEM2 overexpression reduced inflammatory cell infiltration, adipogenesis, and fibrosis in orbital tissues. These findings highlight the varied regulatory role of TMEM2 in GO pathogenesis. Our study reveals that TMEM2 plays a crucial role in mitigating inflammation, suppressing adipogenesis, and reducing fibrosis in GO. TMEM2 has potential as a therapeutic target and biomarker for treating or alleviating GO. These findings advance our understanding of GO pathophysiology and provide opportunities for targeted interventions to modulate TMEM2 for therapeutic purposes. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Hong Li, Jie Min, Yucheng Yang, Wendong Suo, Wei Wang, Jiahe Tian, Yujie Qin. TMEM2 inhibits the development of Graves' orbitopathy through the JAK-STAT signaling pathway. The Journal of biological chemistry. 2024 Feb;300(2):105607