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ResearchIn-Press PreviewBone biologyDevelopment Open Access | 10.1172/jci.insight.183684

Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling

Yi Fan,1 Ping Lyu,1 Jiahe Wang,1 Yali Wei,1 Zucen Li,1 Shiwen Zhang,1 Takehito Ouchi,2 Junjun Jing,1 Quan Yuan,1 Clifford J. Rosen,3 and Chenchen Zhou1

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Fan, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

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1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Wang, J. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Wei, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Li, Z. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Zhang, S. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Ouchi, T. in: JCI | PubMed | Google Scholar |

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Jing, J. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Yuan, Q. in: JCI | PubMed | Google Scholar |

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Rosen, C. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China

2Department of Physiology, Tokyo Dental College, Tokyo, Japan

3Maine Medical Center Research Institute, Scarborough, United States of America

Find articles by Zhou, C. in: JCI | PubMed | Google Scholar

Published December 17, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.183684.
Copyright © 2024, Fan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 17, 2024 - Version history
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Abstract

Regeneration of orofacial bone defects caused by inflammatory-related diseases or trauma remains an unmet challenge. Parathyroid hormone 1 receptor (PTH1R) signaling is a key mediator of bone remodeling whereas the regulatory mechanisms of PTH1R signaling in oral bone under homeostatic or inflammatory conditions have not been demonstrated by direct genetic evidence. Here we observed that deletion of PTH1R in Gli1+-progenitors led to increased osteogenesis and osteoclastogenesis. Single-cell and bulk RNA-seq analysis revealed that PTH1R suppresses the osteogenic potential of Gli1+-progenitors during inflammation. Moreover, we identified upregulated IGF1 expression upon PTH1R deletion. Dual deletion of IGF1 and PTH1R ameliorated the bone remodeling phenotypes in PTH1R-defienct mice. Furthermore, in vivo evidence revealed an inverse relationship between PTH1R and Hedgehog signaling, which was responsible for the upregulated IGF1 production. Our work underscored the negative feedback between PTH1R and IGF1 in craniofacial bone turnover, and revealed mechanisms modulating orofacial bone remodeling.

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