Force-Loaded Cementocytes Regulate Osteoclastogenesis Via S1p/S1pr1/ Rac1 Axis

Aim or purpose: This study elucidates the pivotal role of the sphingosine-1-phosphate (S1P)/S1PR1/Rac1 axis in cementocyte-regulated osteoclastogenesis during orthodontically induced inflammatory root resorption (OIIRR). Materials and methods: IDG-CM6 cementocytes were subjected to physiologic (0.5 g/cm²) or pathologic (3 g/cm²) compressive stress to simulate orthodontic forces. Conditioned media from stressed cells were used to assess osteoclast precursor migration, differentiation, and resorption activity. Molecular mechanisms were probed via siRNA-mediated knockdown of S1PR1/Rac1 and pharmacological inhibitors. In vivo, rat models with 25 g (light) or 100 g (heavy) orthodontic forces were treated with S1PR1/Rac1 inhibitors to evaluate root resorption. Results: Heavy compressive force triggered robust S1P synthesis and secretion in cementocytes, whereas light force suppressed S1P production. High-force conditioned media enhanced osteoclast precursor migration, differentiation, and resorption activity, while light-force media promoted apoptosis. Genetic or pharmacological inhibition of S1PR1/Rac1 abolished osteoclast activation driven by cementocyte-derived S1P. In vivo, heavy orthodontic force induced severe root resorption, which was markedly attenuated by blocking the S1P/S1PR1/Rac1 axis. Crucially, this intervention preserved physiological tooth movement and bone remodeling, demonstrating selective targeting of pathologic resorption without compromising orthodontic efficacy. Conclusions: Cementocytes modulate osteoclastogenesis via compression-dependent S1P secretion. The S1P/S1PR1/Rac1 axis drives orthodontic root resorption, while its inhibition selectively attenuates pathology without compromising orthodontic treatment efficacy, positioning this pathway as a translatable therapeutic target for OIIRR.