Runt-related transcription factor 2 transcriptionally represses Sirtuin 1 to regulate osteoclastogenesis and tooth eruption

Authors

• Jie Li, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of China
• Changqing Yan, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of China
• Xinyi Sun, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of China
• Chenying Zhang, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of China
• Xiaozhe Wang, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of China
• Yang Liu, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of China
• Shuguo Zheng, Department of Preventive Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing, People's Republic of ChinaFollow

Abstract

Background/purpose: Cleidocranial dysplasia (CCD), caused by Runt-related transcription factor 2 (RUNX2) haploinsufficiency, features delayed tooth eruption. Although impaired osteoclastogenesis contributes to eruption failure, the direct molecular mechanisms linking RUNX2 deficiency to osteoclast dysfunction remain elusive. Sirtuin 1 (SIRT1) is a critical regulator of osteoclastogenesis; however, whether it serves as a downstream effector of RUNX2 remains unexplored. This study aimed to elucidate the mechanistic link between RUNX2 and SIRT1 in regulating osteoclast differentiation and tooth eruption.

Materials and methods: Tooth eruption and osteoclast differentiation were assessed by micro-computed tomography and histological analysis in Runx2^+/- mice. Chromatin immunoprecipitation quantitative polymerase chain reaction and luciferase reporter assays confirmed RUNX2 binding to the Sirt1 promoter. Osteoclast marker expression was evaluated by reverse transcription quantitative polymerase chain reaction and western blotting. Bone marrow-derived macrophages from Runx2^+/- mice were transfected with small interfering RNA targeting SIRT1 for rescue experiments. Osteoclast differentiation and function were assessed by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assays.

Results: Runx2^+/- mice showed significantly reduced mandibular first molar eruption and decreased TRAP-positive osteoclasts, accompanied by SIRT1 upregulation. RUNX2 directly bound to the Sirt1 promoter and repressed its transcription. SIRT1 knockdown increased expression levels of osteoclast markers and elevated acetylation of NF-κB p65 at lysine 310. Importantly, SIRT1 knockdown rescued osteoclast formation and resorption to wild-type levels in Runx2^+/- cells.

Conclusion: RUNX2 haploinsufficiency impairs tooth eruption through transcriptional derepression of SIRT1, which inhibits osteoclastogenesis via NF-κB p65 deacetylation, highlighting the RUNX2-SIRT1 axis as a novel therapeutic target for CCD.

Recommended Citation

Li, Jie; Yan, Changqing; Sun, Xinyi; Zhang, Chenying; Wang, Xiaozhe; Liu, Yang; and Zheng, Shuguo (2026) "Runt-related transcription factor 2 transcriptionally represses Sirtuin 1 to regulate osteoclastogenesis and tooth eruption," Journal of Dental Sciences: Vol. 21: Iss. 4, Article 38.
Available at: https://jds.ads.org.tw/journal/vol21/iss4/38

Publication Date

2026