Klotho senses mechanical stimuli and modulates tension-induced osteogenesis

Delicate external mechanosensing, efficient intracellular mechanotransduction and effective alveolar bone remodeling lay the foundation of orthodontic tooth movement (OTM). Periodontal ligament stem cells (PDLSCs) are thought to be the primary cells that withstand mechanical stimuli and respond to biomechanical signals during orthodontic treatment. Nevertheless, the cellular and molecular mechanisms of orthodontic force-induced mechanosignaling and osteogenesis in PDLSCs still remain unclear. In the present study, we hypothesize that the ageing suppressor, Klotho, is correlated with orthodontic force-triggered mechanical signaling cascades, further contributing to alveolar bone remodeling. This study reveals that Klotho expression is notably upregulated via cytoskeletal-nuclei-mediated epigenetic modifications, consistent with osteogenic differentiation on the tension side during OTM. Additionally, Klotho deficiency undermines tensile force-induced new bone formation in NFκB- and PI3K/Akt-dependent manners. Notably, RNA sequencing (RNA-seq) results and targeted force application experiments unveil that Klotho not only functions as a downstream effector of external stress but also acts as an upstream regulator in mechanical signaling for the first time. In summary, we identify the indispensable role of Klotho in mechanotransduction and alveolar bone formation, which provide a latent target of linking cell senescence to mechanical force in future studies and offer novel insights into orthodontic force-induced tooth movement and bone remodeling.