Loss of Sc5d results in micrognathia due to a failure in osteoblast differentiation.

Autor:	Iwaya C; Department of Diagnostic & Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA; Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA., Suzuki A; Department of Diagnostic & Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA; Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA., Iwata J; Department of Diagnostic & Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA; Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054, USA; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: Junichi.Iwata@uth.tmc.edu.
Jazyk:	angličtina
Zdroj:	Journal of advanced research [J Adv Res] 2024 Nov; Vol. 65, pp. 153-165. Date of Electronic Publication: 2023 Dec 10.
DOI:	10.1016/j.jare.2023.12.008
Abstrakt:	Introduction: Mutations in genes related to cholesterol metabolism, or maternal diet and health status, affect craniofacial bone formation. However, the precise role of intracellular cholesterol metabolism in craniofacial bone development remains unclear. Objective: The aim of this study is to determine how cholesterol metabolism aberrations affect craniofacial bone development. Methods: Mice with a deficiency in Sc5d, which encodes an enzyme involved in cholesterol synthesis, were analyzed with histology, micro computed tomography (microCT), and cellular and molecular biological methods. Results: Sc5d null mice exhibited mandible hypoplasia resulting from defects in osteoblast differentiation. The activation of the hedgehog and WNT/β-catenin signaling pathways, which induce expression of osteogenic genes Col1a1 and Spp1, was compromised in the mandible of Sc5d null mice due to a failure in the formation of the primary cilium, a cell surface structure that senses extracellular cues. Treatments with an inducer of hedgehog or WNT/β-catenin signaling or with simvastatin, a drug that restores abnormal cholesterol production, partially rescued the defects in osteoblast differentiation seen in Sc5d mutant cells. Conclusion: Our results indicate that loss of Sc5d results in mandibular hypoplasia through defective primary cilia-mediated hedgehog and WNT/β-catenin signaling pathways. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Production and hosting by Elsevier B.V.)
Databáze:	MEDLINE
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