AGEs impair osteogenesis in orthodontic force-induced periodontal ligament stem cells through the KDM6B/Wnt self-reinforcing loop.

Background: Diabetes, occasionally diagnosed in orthodontic patients, can impede orthodontic tooth movement (OTM) by accumulating advanced glycation end products (AGEs) in the periodontium. This accumulation impairs the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) due to alterations in the force-loaded microenvironment, yet the underlying mechanisms remain elusive.

Methods: Bioinformatics analysis of GSE112122 identified alterations in the mechanical regulation of histone methylation enzyme Lysine Demethylase 6B (KDM6B). OTM models were established in healthy and Nicotinamide/ Streptozotocin-induced type II diabetic rats. The impact of AGEs on mechanically induced osteogenesis and its correlation with KDM6B were evaluated by assessing the therapeutic effects of periodontal ligament injections of the AGEs/RAGE inhibitor FPS-ZM1. To investigate transcriptomic changes, we extracted human PDLSCs, which were subjected to RNA sequencing following the overexpression of KDM6B. Experimental validation further identified potential self-reinforcing loops and their associated antioxidative mechanisms.

Results: Mechanical forces upregulated KDM6B expression and function in PDLSCs, modulating extensive downstream osteogenesis-related transcriptional changes. Experiments with AGEs-treated and FPS-ZM1-treated samples demonstrated that AGEs impaired osteogenesis by compromising KDM6B mechanical responsiveness. A positive feedback loop between KDM6B and Wnt pathways was identified, inhibited by AGEs. This loop regulated superoxide dismutase 2 (SOD2), facilitating antioxidative stress and preventing stem cell ageing.

Conclusions: This study elucidates a novel mechanism by which AGEs influence the osteogenic process and antioxidative capacity of PDLSCs through the KDM6B/Wnt self-reinforcing loop under orthodontic force. Targeting the AGE/RAGE pathway or enhancing KDM6B may enhance orthodontic treatments for diabetic patients.