Mechano-responsive microRNA-functionalized PDLSC exosomes as a novel therapeutic for inflammatory bone loss in periodontitis

Abstract

Biomechanical stimulation is crucial for the regulation of osteogenesis in the alveolar bone. Periodontal Ligament Stem Cells (PDLSCs) are the sensor for mechanical stimulation during orthodontic tooth movement and regulators of alveolar bone remodeling through the paracrine effect. Our previous findings confirmed that tension stimulation on PDLSCs enhanced the osteogenic induction properties of exosomes (Exos). This study aims to explore the mechanism of tension-stimulated PDLSC Exos to regulate osteogenesis and develop a strategy to functionalize Exos for the treatment of bone loss in periodontitis. Here, by comparing the elevated miRNAs in the exosomes (Exos) secreted by the PDLSCs after tension stimulation, we found miR-200 family were mechano-responsive miRNAs in Exos. miR-200b/c carried by Exos secreted by strain Mechanical stimulated PDLSCs can be taken up by human mandibular BMSCs under tension, resulting in a bone-promoting effect. Through bioinformatics target prediction and verification through gain-and loss-of-function assays, we confirmed that miR-200b/c targeted Smurf1 to activate the BMP-Smad signaling pathway and promote osteogenic differentiation of mandibular BMSCs. Finally, a rat model of alveolar bone defect was applied to evaluate the therapeutic effect of functionalized Exos on bone formation in vivo. Histological analysis confirmed that miR-200b/c functionalized Exos could efficiently promote the repair of alveolar bone defects, suggesting a novel therapeutic for inflammatory bone loss in periodontitis.