Inflammatory bone loss and signaling pathways in periodontitis: mechanistic insights and emerging therapeutic strategies

Bone resorption is a vital physiological process that enables skeletal remodeling, maintenance, and adaptation to mechanical forces throughout life. While tightly regulated under the physiological state, its dysregulation contributes to pathological conditions such as osteoporosis, rheumatoid arthritis, and periodontitis. Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome, leading to the progressive breakdown of the periodontal ligament, cementum, and alveolar bone and ultimately resulting in tooth loss. This review outlines the molecular and cellular mechanisms underlying periodontitis, focusing on osteoclastogenesis, the differentiation and activation of osteoclasts, the primary mediators of bone resorption. Key transcriptional regulators, including NFATc1, c-Fos, and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase (MAPK), Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Nuclear Factor Kappa B (NF-κB), and Phosphoinositide 3-kinase (PI3K)/Akt, to elucidate their roles in the initiation and progression of periodontal bone loss. These pathways orchestrate the inflammatory response and osteoclast activity, underscoring their relevance in periodontitis and other osteolytic conditions. Hallmark features of periodontitis, including chronic inflammation, immune dysregulation, and tissue destruction are highlighted, with emphasis on current and emerging therapeutic strategies targeting these molecular pathways. Special attention is given to small molecules, biologics, and natural compounds that have the potential to modulate key signaling pathways. Although advances in understanding these mechanisms have identified promising therapeutic targets, translation into effective clinical interventions remains challenging. Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone diseases.