State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, Sichuan, China.
Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 510055, Guangzhou, Guangdong, China.
Signal Transduct Target Ther. 2022 May 11;7(1):155. doi: 10.1038/s41392-022-00957-5.
Maxillofacial bone defects are commonly seen in clinical practice. A clearer understanding of the regulatory network directing maxillofacial bone formation will promote the development of novel therapeutic approaches for bone regeneration. The fibroblast growth factor (FGF) signalling pathway is critical for the development of maxillofacial bone. Klotho, a type I transmembrane protein, is an important components of FGF receptor complexes. Recent studies have reported the presence of Klotho expression in bone. However, the role of Klotho in cranioskeletal development and repair remains unknown. Here, we use a genetic strategy to report that deletion of Klotho in Osx-positive mesenchymal progenitors leads to a significant reduction in osteogenesis under physiological and pathological conditions. Klotho-deficient mensenchymal progenitors also suppress osteoclastogenesis in vitro and in vivo. Under conditions of inflammation and trauma-induced bone loss, we find that Klotho exerts an inhibitory function on inflammation-induced TNFR signaling by attenuating Rankl expression. More importantly, we show for the first time that Klotho is present in human alveolar bone, with a distinct expression pattern under both normal and pathological conditions. In summary, our results identify the mechanism whereby Klotho expressed in Osx-mensenchymal progenitors controls osteoblast differentiation and osteoclastogenesis during mandibular alveolar bone formation and repair. Klotho-mediated signaling is an important component of alveolar bone remodeling and regeneration. It may also be a target for future therapeutics.
颌面部骨缺损在临床实践中很常见。更清楚地了解指导颌面部骨形成的调控网络将促进骨再生的新治疗方法的发展。成纤维细胞生长因子（FGF）信号通路对颌面部骨的发育至关重要。Klotho 是一种 I 型跨膜蛋白，是 FGF 受体复合物的重要组成部分。最近的研究报告称 Klotho 在骨中表达。然而，Klotho 在颅颌面发育和修复中的作用尚不清楚。在这里，我们使用遗传策略报告 Klotho 在 Osx 阳性间充质祖细胞中的缺失导致在生理和病理条件下成骨作用显著降低。Klotho 缺陷的间充质祖细胞也在体外和体内抑制破骨细胞生成。在炎症和创伤性骨丢失的情况下，我们发现 Klotho 通过减弱 Rankl 表达对炎症诱导的 TNFR 信号发挥抑制作用。更重要的是，我们首次表明 Klotho 存在于人类牙槽骨中，在正常和病理条件下具有明显的表达模式。总之，我们的结果确定了 Klotho 在 Osx 间充质祖细胞中表达的机制，该机制控制下颌牙槽骨形成和修复过程中的成骨细胞分化和破骨细胞生成。Klotho 介导的信号是牙槽骨重塑和再生的重要组成部分。它也可能是未来治疗的靶点。
