Axin2+ PDL Cells Directly Contribute to New Alveolar Bone Formation in Response to Orthodontic Tension Force

Abstract

Wnt–β-catenin signaling plays a key role in orthodontic tooth movement (OTM), a common clinical practice for malocclusion correction. However, its targeted periodontal ligament (PDL) progenitor cells remain largely unclear. In this study, we first showed a synchronized increase in Wnt–β-catenin levels and Axin2+ PDL progenitor cell numbers during OTM using immunostaining of β-catenin in wild-type mice and X-gal staining in the Axin2-LacZ knock-in line. Next, we demonstrated time-dependent increases in Axin2+ PDL progenitors and their progeny cell numbers within PDL and alveolar bones during OTM using a one-time tamoxifen-induced Axin2 tracing line ( Axin2CreERT2/+; R26RtdTomato/+). Coimmunostaining images displayed both early and late bone markers (such as RUNX2 and DMP1) in the Axin2Lin PDL cells. Conversely, ablation of Axin2+ PDL cells via one-time tamoxifen-induced diphtheria toxin subunit A (DTA) led to a drastic decrease in osteogenic activity (as reflected by alkaline phosphatase) in PDL and alveolar bone. There was also a decrease in new bone mass and a significant reduction in the mineral apposition rate on both the control side (to a moderate degree) and the OTM side (to a severe degree). Thus, we conclude that the Axin2+ PDL cells (the Wnt-targeted key cells) are highly sensitive to orthodontic tension force and play a critical role in OTM-induced PDL expansion and alveolar bone formation. Future drug development targeting the Axin2+ PDL progenitor cells may accelerate alveolar bone formation during orthodontic treatment.

Diverse stem cells for periodontal tissue formation and regeneration

“…Axin2 is a direct target of Wnt signaling (Jho et al, 2002;Lustig et al, 2002) and Wnt-responsive cells expressing Axin2 are identified as MSCs in various tissues, including the dental pulp of both mouse incisors and molars in mice (Yuan et al, 2018) and during orthodontic tooth movement (K. Wang et al, 2022). In cementogenesis, Axin2 + cells differentiate into cementoblasts under the regulation of Wnt signaling (Xie et al, 2019), in a similar manner to Gli1 + cells (Xie et al, 2021).…”

“…Axin2 is a direct target of Wnt signaling (Jho et al, 2002; Lustig et al, 2002) and Wnt‐responsive cells expressing Axin2 are identified as MSCs in various tissues, including the dental pulp of both mouse incisors and molars in mice (An et al, 2018; Babb, Chandrasekaran, Carvalho Moreno Neves, & Sharpe, 2017; Bowman, van Amerongen, Palmer, & Nusse, 2013; Lee et al, 2015; van Amerongen, Bowman, & Nusse, 2012). Axin2 + cells in the PDL differentiate into alveolar bone osteoblasts after tooth extraction (Yuan et al, 2018) and during orthodontic tooth movement (K. Wang et al, 2022). In cementogenesis, Axin2 + cells differentiate into cementoblasts under the regulation of Wnt signaling (Xie et al, 2019), in a similar manner to Gli1 + cells (Xie et al, 2021).…”

Advances in periodontal stem cells and the regulating niche: From in vitro to in vivo

“…Wnt3A protein applied in the extraction socket increased the number of Wnt‐responsive cells and facilitated bone formation (Yuan et al, 2018). Axin2+ cells in the periodontal tissue were sensitive to orthodontic tension force and were involved with PDL expansion and alveolar bone formation (K. Wang et al, 2022). Furthermore, Axin2+ cells were shown to support postnatal cementogenesis (Xie et al, 2021).…”

Mammalian Sirtuins and Their Relevance in Vascular Calcification

“…Through this pathway, the increased expression of SIRT1 suppressed Wnt/β-catenin signaling and further inhibited VC ( Chen et al, 2021a ). And Wnt/β-catenin is well verified to play an important role in osteogenesis calcification and alveolar bone remodeling ( Wang et al, 2022 ). Similarly, SIRT1 signaling has been found to be activate during the resveratrol-induced improvement of aortic calcification in ovariectomized rats ( Hammad et al, 2021 ).…”