From force to resorption: mechanotransduction, osteoclasts, prevention

Orthodontically induced root resorption (OIRR) is a frequent and often irreversible complication of orthodontic treatment, characterized by the pathological loss of hard root tissue under sustained mechanical loading. The risk and severity of OIRR reflect the interplay between mechanical variables (force magnitude, direction, and duration) and patient-specific biological susceptibility. Osteoclasts and osteoclast-like cells on the root surface are the principal effectors of pathological root loss and act in concert with periodontal ligament cells, cementoblasts, osteocytes, and immune populations to generate a local pro-resorptive microenvironment. Mechanical signals are transduced into biochemical cues that engage canonical osteoclastogenesis pathways (RANK/RANKL/osteoprotegerin, MAPK, nuclear factor-κB), and modulatory processes including epigenetic regulation, autophagy/apoptosis balance, reactive oxygen species dynamics, and extracellular matrix remodeling. Systemic factors (hormonal and metabolic status and genetic predisposition) further modify individual susceptibility and therapeutic responses. This review synthesizes current knowledge on the molecular and cellular cascades linking orthodontic force to osteoclastic activation and root resorption and examines how intercellular communication shapes spatial and temporal patterns of tissue breakdown. We critically appraise emerging diagnostics for the early detection of root resorption and evaluate translational therapeutic strategies, including the local delivery of osteoclast inhibitors and biomaterial-based carriers for gene- and cell-based approaches. These strategies aim to selectively suppress pathological root resorption while preserving the alveolar bone remodeling necessary for efficient tooth movement. Taken together, this review discusses the key cellular and molecular regulatory networks involved in OIRR with osteoclasts as the central focus, and outlines future directions, including multi-omics approaches to resolve cellular subpopulation dynamics and the development of local delivery systems targeting osteoclasts.