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

Yi Fan, 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.
Chen Cui, 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.
Clifford J. Rosen, Maine Medical Center Research Institute, Scarborough, ME, 04074, USA.Follow
Tadatoshi Sato, Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02215, USA.
Ruoshi Xu, 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.
Peiran Li, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, Sichuan, China.
Xi Wei, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 510055, Guangzhou, Guangdong, China.
Ruiye Bi, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, Sichuan, China.
Quan Yuan, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, Sichuan, China. Yuanquan@scu.edu.cn.
Chenchen Zhou, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, Sichuan, China. chenchenzhou5510@scu.edu.cn.

Document Type

Article

Publication Date

5-11-2022

Institution/Department

Maine Medical Center Research Institute

Journal Title

Signal transduction and targeted therapy

MeSH Headings

Bone Development (physiology); Bone and Bones (cytology, metabolism); Fibroblast Growth Factors (metabolism); Humans; Inflammation (genetics, metabolism, pathology); Klotho Proteins (metabolism); Maxilla (growth & development, metabolism); Mesenchymal Stem Cells (cytology, metabolism); Osteogenesis (genetics); Sp7 Transcription Factor

Abstract

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.

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155

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