TY - JOUR

T1 - Association of G protein-coupled receptor 78 with salivary dysfunction in male Sjögren's patients

AU - Tanaka, Tsutomu

AU - Guimaro, Maria C.

AU - Nakamura, Hiroyuki

AU - Perez, Paola

AU - Ji, Youngmi

AU - Michael, Drew G.

AU - Afione, Sandra A

AU - Zheng, Changyu

AU - Goldsmith, Corinne

AU - Swaim, William D

AU - Pedersen, Anne Marie Lynge

AU - Chiorini, John A.

N1 - This article is protected by copyright. All rights reserved.

PY - 2024

Y1 - 2024

N2 - OBJECTIVE: Sjögren's disease (SjD) has a strong sex bias, suggesting an association with sex hormones. Male SjD represents a distinct subset of the disease, but the pathogenic mechanisms of male SjD is poorly characterized. The aim of this study is to identify initiating events related to the development of gland hypofunction and autoimmunity in male SjD patients.MATERIALS AND METHODS: Human minor salivary glands were transcriptomically analyzed with microarrays to detect differentially expressed genes in male SjD patients. Identified genes were tested on their involvement in the disease using conditional transgenic mice and gene-overexpressing cells.RESULTS: GPR78, an orphan G protein-coupled receptor, was overexpressed in salivary glands of male SjD patients compared with male healthy controls and female SjD patients. Male GPR78 transgenic mice developed salivary gland hypofunction with increased epithelial apoptosis, which were not seen in control or female transgenic mice. In cell culture, GPR78 overexpression decreased lysosomal integrity, leading to caspase-dependent apoptotic cell death. GPR78-induced cell death in vitro was inhibited by treatment with estradiol.CONCLUSION: GPR78 overexpression can induce apoptosis and salivary gland hypofunction in male mice through lysosomal dysfunction and increased caspase-dependent apoptosis in salivary gland epithelium, which may drive disease in humans.

AB - OBJECTIVE: Sjögren's disease (SjD) has a strong sex bias, suggesting an association with sex hormones. Male SjD represents a distinct subset of the disease, but the pathogenic mechanisms of male SjD is poorly characterized. The aim of this study is to identify initiating events related to the development of gland hypofunction and autoimmunity in male SjD patients.MATERIALS AND METHODS: Human minor salivary glands were transcriptomically analyzed with microarrays to detect differentially expressed genes in male SjD patients. Identified genes were tested on their involvement in the disease using conditional transgenic mice and gene-overexpressing cells.RESULTS: GPR78, an orphan G protein-coupled receptor, was overexpressed in salivary glands of male SjD patients compared with male healthy controls and female SjD patients. Male GPR78 transgenic mice developed salivary gland hypofunction with increased epithelial apoptosis, which were not seen in control or female transgenic mice. In cell culture, GPR78 overexpression decreased lysosomal integrity, leading to caspase-dependent apoptotic cell death. GPR78-induced cell death in vitro was inhibited by treatment with estradiol.CONCLUSION: GPR78 overexpression can induce apoptosis and salivary gland hypofunction in male mice through lysosomal dysfunction and increased caspase-dependent apoptosis in salivary gland epithelium, which may drive disease in humans.

U2 - 10.1111/odi.14506

DO - 10.1111/odi.14506

M3 - Journal article

C2 - 36652502

VL - 30

SP - 1173

EP - 1182

JO - Oral Diseases

JF - Oral Diseases

SN - 1354-523X

IS - 3

ER -