Family with sequence similarity 20‑member C (FAM20C), a recently characterized Golgi kinase, performs numerous biological functions by phosphorylating more than 100 secreted proteins. However, the role of FAM20C in the salivary glands remains undefined. The present study demonstrated that FAM20C is mainly located in the cytoplasm of duct epithelial cells in the salivary glands. Fam20cf/f; Mmtv‑Cre mice were created in which Fam20c was inactivated in the salivary gland cells and observed that the number of ducts and the ductal cross‑sectional area increased significantly, while the number of acinar cells was reduced. The granular convoluted tubules (GCTs) exhibited an accumulation of aberrant secretory granules, along with a reduced expression and altered distribution patterns of β nerve growth factor, α‑amylase and bone morphogenetic protein (BMP) 4. This abnormality suggested that the GCT cells were immature and exhibited defects in developmental and secretory functions. In accordance with the morphological alterations and the reduced number of acinar cells, FAM20C deficiency in the salivary glands significantly decreased the salivary flow rate. The Na+, Cl– and K+ concentrations in the saliva were all significantly increased due to dysfunction of the ducts. Furthermore, Fam20c deficiency significantly increased BMP2 and BMP7 expression, decreased BMP4 expression, and attenuated the canonical and noncanonical BMP signaling pathways in the salivary glands. Collectively, the results of the present study demonstrate that FAM20C is a key regulator of acinar and duct structure and duct maturation and provide a novel avenue for investigating novel therapeutic targets for oral diseases including xerostomia.
FAM20C is elevated in inflamed periodontal tissues and LPS-treated cells. • Fam20c loss sensitizes osteoblasts to Caspase-1/GSDMD pyroptosis. • RNA-seq links Fam20c deficiency to pyroptosis and ER-stress signatures. • Metabolomics reveals purine and amino-acid metabolic remodelling. • Ac-YVAD-CMK reverses inflammatory activation in Fam20c-deficient cells. FAM20C is a secretory-pathway kinase required for mineralized-tissue homeostasis, and FAM20C-associated disease is accompanied by early periodontal inflammation. We investigated whether FAM20C limits Caspase-1-dependent osteoblast pyroptosis during periodontal inflammatory challenge. FAM20C/Fam20c expression was assessed by immunohistochemistry in ligature-induced mouse periodontitis and human gingiva and by RT-qPCR after lipopolysaccharide (LPS) exposure in four cell models. Stable Fam20c-deficient and Fam20c-overexpressing osteoblasts were analysed by transcriptomics, untargeted metabolomics, microscopy, immunofluorescence, RT-qPCR, Western blotting, ELISA and pharmacological Caspase-1 inhibition. FAM20C/Fam20c protein and mRNA increased in inflamed tissues, and LPS induced Fam20c expression. Fam20c deficiency increased ER-stress/Ca 2+ -homeostasis and inflammasome/pyroptosis module scores, reduced osteogenic gene expression and altered purine- and antioxidant-related metabolites. Fam20c loss enhanced LPS-induced cleaved Caspase-1, N-GSDMD and IL-1β/IL-18 release, whereas Fam20c overexpression attenuated these responses. Ac-YVAD-CMK reduced Caspase-1/GSDMD activation and cytokine release in Fam20c-deficient cells. These findings identify Fam20c as a determinant of osteoblast susceptibility to Caspase-1-dependent pyroptosis. Periodontal LPS induces an early FAM20C stress response. Genetic Fam20c deficiency disrupts ER/Ca 2+ and metabolic homeostasis, increases Caspase-1 activation and GSDMD cleavage, and amplifies osteoblast pyroptosis. Ac-YVAD-CMK reduces Caspase-1/GSDMD activation and cytokine release Download: Download high-res image (290KB) Download: Download full-size image
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