Runt-related transcription factor 2 transcriptionally represses sirtuin 1 to regulate osteoclastogenesis and tooth eruption.
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 microcomputed 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.
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BibTeX
@article{li2026runtrelated,
title = {{Runt-related transcription factor 2 transcriptionally represses sirtuin 1 to regulate osteoclastogenesis and tooth eruption.}},
author = {Jie Li and Changqing Yan and Xinyi Sun and Chenying Zhang and Xiaozhe Wang and Yang Liu and Shuguo Zheng},
journal = {Journal of dental sciences},
year = {2026},
month = oct,
doi = {10.1016/j.jds.2025.07.3510},
url = {https://europepmc.org/article/MED/42924197},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Runt-related transcription factor 2 transcriptionally represses sirtuin 1 to regulate osteoclastogenesis and tooth eruption.
AU - Jie Li
AU - Changqing Yan
AU - Xinyi Sun
AU - Chenying Zhang
AU - Xiaozhe Wang
AU - Yang Liu
AU - Shuguo Zheng
PY - 2026
DA - 2026/10/01
JO - Journal of dental sciences
DO - 10.1016/j.jds.2025.07.3510
UR - https://europepmc.org/article/MED/42924197
AB - 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 microcomputed 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.
SN - 1991-7902
SN - 2213-8862
ER -