Klotho in Osx+-mesenchymal progenitors exerts pro-osteogenic and anti-inflammatory effects during mandibular alveolar bone formation and repair

• Published in: Signal transduction and targeted therapy Vol. 7; no. 1; p. 155
• Main Authors: Fan, Yi, Cui, Chen, Rosen, Clifford J., Sato, Tadatoshi, Xu, Ruoshi, Li, Peiran, Wei, Xi, Bi, Ruiye, Yuan, Quan, Zhou, Chenchen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-05-2022; Nature Publishing Group
• Subjects: 631/136/142; 631/136/815; 692/163/2743; 692/420/256; Ablation; Alveolar bone; Bone and Bones - cytology; Bone and Bones - metabolism; Bone Development - physiology; Bone growth; Bone loss; Bone remodeling; Cancer Research; Cell Biology; Clinical medicine; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Fibroblasts; Genotype & phenotype; Growth factors; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Internal Medicine; Klotho protein; Klotho Proteins - metabolism; Laboratories; Mandible; Maxilla - growth & development; Maxilla - metabolism; Maxillofacial; Medicine; Medicine & Public Health; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchyme; Oncology; Oral diseases; Osteoblastogenesis; Osteoclastogenesis; Osteogenesis; Osteogenesis - genetics; Osteoprogenitor cells; Pathology; Physiology; Regeneration; Research centers; Signal transduction; Sp7 Transcription Factor; TRANCE protein; Trauma; Tumor necrosis factor receptors
• ISSN: 2059-3635; 2095-9907; 2059-3635
• 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.