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

Yi Fan, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Ping Lyu, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Jiahe Wang, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Yali Wei, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Zucen Li, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Shiwen Zhang, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Takehito Ouchi, Department of Physiology, Tokyo Dental College, Tokyo, Japan.
Junjun Jing, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Quan Yuan, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Chenchen Zhou, State Key Laboratory of Oral Diseases, National Center for Stomatology, Nat, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Clifford J. Rosen, MaineHealth Institute for Research, Scarborough, ME.Follow

Document Type

Article

Publication Date

12-17-2024

Institution/Department

Center for Clinical and Translational Science

Journal Title

JCI insight

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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