FRZB regulates the osteogenic differentiation of periodontal ligament stem cells in an inflammatory microenvironment through Wnt5a-mitochondrial axis.

The Wnt signaling pathway critically regulates the osteogenic differentiation in periodontal ligament stem cells (PDLSCs). However, the functional contributions of this pathway under inflammatory conditions remain unclear. This study investigated the effect and underlying mechanisms of the FRZB-Wnt5a-mitochondrial axis on the osteogenic differentiation capacity of PDLSCs under inflammatory conditions. PDLSCs were isolated from healthy teeth and exposed to lipopolysaccharide (LPS) to mimic an inflammatory microenvironment. The Wnt pathway-related molecules were assessed, and the osteogenic differentiation capacity and mitochondrial function of PDLSCs were evaluated. To elucidate its regulatory role, we employed gene transfection to establish an FRZB (Frizzled-Related Protein) overexpression model. Results showed that inflammation significantly impaired osteogenic differentiation and activated Wnt/β-catenin signaling. Mitochondrial dysfunction was also observed, including reduced membrane potential, increased calcium and reactive oxygen species (ROS) levels, suppressed autophagic flux, and altered mitochondrial morphology. Notably, FRZB overexpression partially restored mitochondrial function and the osteogenic differentiation capacity of PDLSCs. These results demonstrated that FRZB serves as a pivotal regulator of osteogenic differentiation in PDLSCs. We found that inflammation downregulates FRZB expression, thereby activating Wnt/β-catenin signaling, which leads to mitochondrial dysfunction and ultimately impairs osteogenesis. These findings reveal a mechanism by which inflammation suppresses osteogenesis in PDLSCs and highlight FRZB as a promising therapeutic target for periodontitis.