Alveolar bone (AB) remodeling, including formation and absorption, is the foundation of orthodontic tooth movement (OTM). However, the sources and mechanisms underlying new bone formation remain unclear. Therefore, we aimed to understand the potential mechanism of bone formation during OTM, focusing on the leptin receptor+ (Lepr+) osteogenitors and periodontal ligament cells (PDLCs). We demonstrated that Lepr+ cells activated by force-induced PDLC apoptosis served as distinct osteoprogenitors during orthodontic bone regeneration. We investigated bone formation both in vivo and in vitro. Single-cell RNA sequencing analysis and lineage tracing demonstrated that Lepr represents a subcluster of stem cells that are activated and differentiate into osteoblasts during OTM. Targeted ablation of Lepr+ cells in a mouse model disrupted orthodontic force–guided bone regeneration. Furthermore, apoptosis and sequential fluorescent labeling assays revealed that the apoptosis of PDLCs preceded new bone deposition. We found that PDL stem cell–derived apoptotic vesicles activated Lepr+ cells in vitro. Following apoptosis inhibition, orthodontic force–activated osteoprogenitors and osteogenesis were significantly downregulated. Notably, we found that bone formation occurred on the compression side during OTM; this has been first reported here. To conclude, we found a potential mechanism of bone formation during OTM that may provide new insights into AB regeneration.

中文翻译：

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正畸中牙周膜细胞凋亡激活 Lepr+ 骨祖细胞


牙槽骨（AB）重塑，包括形成和吸收，是正畸牙齿移动（OTM）的基础。然而，新骨形成的来源和机制仍不清楚。因此，我们旨在了解 OTM 期间骨形成的潜在机制，重点关注瘦素受体+（Lepr+）成骨细胞和牙周膜细胞（PDLC）。我们证明，由力诱导的 PDLC 凋亡激活的 Lepr+ 细胞在正畸骨再生过程中充当独特的骨祖细胞。我们研究了体内和体外的骨形成。单细胞 RNA 测序分析和谱系追踪表明，Lepr 代表干细胞亚群，在 OTM 期间被激活并分化为成骨细胞。小鼠模型中 Lepr+ 细胞的靶向消融破坏了正畸力引导的骨再生。此外，细胞凋亡和连续荧光标记测定表明，PDLC 的细胞凋亡先于新骨沉积。我们发现 PDL 干细胞衍生的凋亡囊泡在体外激活 Lepr+ 细胞。细胞凋亡抑制后，正畸力激活的骨祖细胞和骨生成显着下调。值得注意的是，我们发现 OTM 期间骨形成发生在受压侧；这是在这里首次报道的。总之，我们发现了 OTM 期间骨形成的潜在机制，这可能为 AB 再生提供新的见解。