Down-regulation of GPRC5A Confers Protection Against Periodontitis

Periodontitis, a common chronic inflammatory disease, causes connective tissue degradation, alveolar bone resorption, and tooth loss. G protein coupled receptor class C group 5 member A (GPRC5A) regulates chronic inflammation in several diseases, but its role in periodontitis remains unclear. This study investigated GPRC5A expression and function in periodontitis. In human tissues, GPRC5A expression was assessed by immunohistochemistry and quantitative real-time PCR (qRT-PCR). In vivo, adeno associated virus (AAV) mediated GPRC5A silencing was applied in a murine periodontitis model. In vitro, mechanistic studies used small interfering RNA (siRNA) knockdown, co-immunoprecipitation (Co-IP), mass spectrometry, and western blot in periodontal ligament cells (PDLCs). GPRC5A was upregulated in inflamed periodontal tissues, and its downregulation reduced alveolar bone loss and periodontitis severity in mice. GPRC5A knockdown suppressed inflammatory cytokine production and NF-κB activation in lipopolysaccharide (LPS) stimulated PDLCs. β-arrestin 2 (ARRB2) expression paralleled GPRC5A changes, and mass spectrometry/Co-IP identified eukaryotic elongation factor 2 (EEF2) as an ARRB2 binding partner. GPRC5A silencing reduced LPS induced ARRB2 expression and EEF2 phosphorylation. These data suggest a possible mechanistic link that GPRC5A downregulation mitigates periodontitis through the ARRB2‑EEF2 pathway, though direct evidence of causality is still needed.