Hyperparathyroidism drives periodontitis progression via parathyroid hormone-induced endoplasmic reticulum stress

Given the high prevalence of periodontitis and potential for undetected primary hyperparathyroidism (pHPT) to exacerbate periodontal damage, managing pHPT in advanced periodontitis (stages III/IV) is critical. The causal link between pHPT and periodontitis remains unclear. This study aims to investigate the causal effect and mechanisms between hyperparathyroidism and periodontitis.

A two-sample Mendelian randomization study used genome-wide association studies (GWAS) summary data to explore the causal link between hyperparathyroidism and periodontitis, employing single nucleotide polymorphisms (SNPs) as instrumental variables and methods like MR-Egger regression and Weighted median for robust results. PTH levels were detected on samples from both healthy and periodontitis-affected gingival tissues and gingival crevicular fluids. We assessed the impact of PTH on periodontal inflammation through treating gingival fibroblasts with PTH and detecting endoplasmic reticulum stress-related markers. Transcriptomics and metabolomics analyses were integrated to explore genetic pathways related to PTH.

Hyperparathyroidism increased the risk of periodontitis, but analyses of periodontitis on hyperparathyroidism showed no reverse causality. PTH levels increased in gingival tissues and gingival crevicular fluid. Multi-omics analysis revealed significant gene and metabolite enrichment in calcium signaling and parathyroid hormone pathways. Since calcium ions are mainly from the endoplasmic reticulum, we focused on endoplasmic reticulum stress and found its effect on lessening PTH-induced periodontal inflammation.

This study suggests that periodontitis may serve as a warning sign for pHPT, highlighting the importance of screening for hyperparathyroidism in periodontitis patients. The principal molecules involved in the endoplasmic reticulum stress pathway present promising therapeutic targets for improving periodontal health in patients with hyperparathyroidism.