Myeloid‐Derived Grancalcin Promotes Periodontal Inflammation and Pathological Bone Remodeling in Periodontitis

ABSTRACT Periodontitis is a common chronic oral inflammatory disease characterized by enhanced inflammation and alveolar bone loss, yet its underlying mechanisms remain incompletely understood. Here, we identified grancalcin (GCA), a protein secreted by myeloid‐derived cells, as significantly enriched in the gingival tissues of both human patients and mouse models of periodontitis. Genetic ablation of GCA, either through global knockout or myeloid‐specific conditional deletion, markedly alleviated periodontal inflammation and pathological bone remodeling. Mechanistically, in primary human gingival fibroblasts, GCA interacts with CD44, which subsequently activates nonmuscle myosin heavy chain IIA (MYH9). MYH9 drives NF‐κB pathway activation and the consequent inflammatory response by promoting the nuclear translocation of its subunit p65, ultimately leading to exacerbated gingival inflammation and pathological bone resorption. Given that a GCA‐neutralizing antibody mitigated these pathogenic processes, we developed a thermosensitive hydroxybutyl chitosan hydrogel for its controlled local delivery, which successfully alleviated periodontitis. Collectively, our findings unveil GCA as a previously unrecognized regulator of periodontitis and highlight its potential as both a molecular marker and a therapeutic target for this disease.