Periodontitis as a Model for Inflammatory Uncoupling of Bone Remodeling.

Periodontitis is traditionally regarded as an oral biofilm-driven inflammatory disease that leads to progressive loss of the tooth-supporting alveolar bone. However, accumulating evidence indicates that periodontal bone loss is more accurately understood as a state of pathological uncoupling of bone remodeling, in which exaggerated bone resorption coexists with inadequate bone formation response. In this review, we reposition periodontitis within the broader context of inflammatory skeletal diseases and synthesize current mechanistic insights from osteoimmunology, bone biology, and mechanobiology. We discuss how excessive osteoclastogenesis in periodontitis is sustained by receptor activator of nuclear factor kappa-B ligand (RANKL) dominance derived from osteocytes, osteoblast-lineage cells, stromal cells, monocytes/macrophages, B and T lymphocytes, and neutrophils within a cytokine-rich microenvironment characterized by tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17A signaling. Persistent activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways further enhance osteoclast differentiation, survival, and resorptive activity. At the same time, inflammatory mediators actively suppress osteoblast-lineage commitment by inhibiting Runx2 and Osterix, antagonizing canonical Wnt/β-catenin signaling through the upregulation of sclerostin and Dickkopf-1 (DKK1), and impairing bone matrix production and mineralization. We further examine how disruption of key osteoclast-osteoblast coupling mechanisms, including ephrinB2/EphB4 and semaphorin signaling, prevents the effective transition from resorption to formation, while osteocyte dysfunction amplifies the uncoupled phenotype by integrating inflammatory and mechanical signals. Comparisons with rheumatoid arthritis, inflammatory bowel disease-associated bone loss, and peri-implantitis reveal shared immune-driven mechanisms of remodeling imbalance, whereas the unique features of alveolar bone, including high turnover, continuous mechanical loading, and chronic microbial exposure, make it particularly susceptible to inflammatory uncoupling. Together, these concepts support a therapeutic shift toward restoring physiological coupling instead of solely inhibiting resorption and position periodontitis as a clinically accessible model for understanding and targeting inflammatory bone loss across skeletal diseases.