CKAP4 Regulates ERS ‐Induced Apoptosis in Osteoclasts Through FOXO3 in Periodontitis

Periodontitis is a prevalent oral disease characterised by chronic inflammation and irreversible alveolar bone loss. Osteoclasts (OCs) are the key cells mediating bone resorption and their excessive formation disrupts bone homeostasis. Since apoptosis of OCs normally restrains this process, its failure can sustain bone loss. However, its role in periodontitis remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data retrieved from the Gene Expression Omnibus (GEO) database revealed impaired OC apoptosis in the periodontal tissues of individuals suffering from periodontitis. Notably, we observed a reduction in cytoskeleton-associated protein 4 (CKAP4) expression correlating with decreased OC apoptosis. Further investigations using Ckap4 knockout mice confirmed that CKAP4 promotes OC apoptosis through the activation of forkhead box O3 (FOXO3)-induced endoplasmic reticulum stress (ERS). CKAP4 regulates OC apoptosis to maintain periodontal homeostasis and its downregulation in periodontitis promotes pathological bone resorption. This study elucidates CKAP4-mediated apoptotic pathways in OCs, providing mechanistic insight and potential therapeutic strategies to restore OC balance and prevent bone loss.