Axin2‐expressing cells in the periodontal ligament are regulated by bone morphogenetic protein signalling and play a pivotal role in periodontium development

Abstract Aim To date, controversies still exist regarding the exact cellular origin and regulatory mechanisms of periodontium development, which hinders efforts to achieve ideal periodontal tissue regeneration. Axin2‐expressing cells in the periodontal ligament (PDL) have been shown to be a novel progenitor cell population that is essential for periodontal homeostasis. In the current study, we aimed to elucidate the regulatory role of bone morphogenetic protein receptor type 1A (BMPR1A)‐mediated BMP signalling in Axin2‐expressing cells during periodontium development. Materials and Methods Two strains of Axin2 gene reporter mice, Axin2 lacZ/+ and Axin2 CreERT2/+ ; R26R tdTomato/+ mice, were used. We next generated Axin2 CreERT2/+ ; R26R DTA/+ ; R26R tdTomato/+ mice to genetically ablate of Axin2‐lineage cells. Axin2 CreERT2/+ ; Bmpr1a fl/fl ; R26R tdTomato/+ mice were established to conditionally knock out Bmpr1a in Axin2‐lineage cells. Multiple approaches, including micro‐computed tomography, calcein green, and alizarin red double‐labelling, scanning electron microscopy, and histological and immunostaining assays, were used to analyse periodontal phenotypes and molecular mechanisms. Results X‐gal staining revealed that Axin2‐expressing cells in the PDL were mainly distributed along the alveolar bone and cementum surface. Cell lineage tracing and cell ablation assays further demonstrated the indispensable role of Axin2‐expressing cells in periodontium development. Next, we found that conditional knockout of Bmpr1a in Axin2‐lineage cells led to periodontal defects, which were characterized by alveolar bone loss, impaired cementogenesis, and abnormal Sharpey's fibres. Conclusions Our findings suggest that Axin2‐expressing cells in the PDL are essential for periodontium development, which is regulated by BMP signalling.