Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling
Yi Fan, Ping Lyu, Jiahe Wang, Yali Wei, Zucen Li, Shiwen Zhang, Takehito Ouchi, Junjun Jing, Quan Yuan, Clifford J. Rosen, Chenchen Zhou
Yi Fan, Ping Lyu, Jiahe Wang, Yali Wei, Zucen Li, Shiwen Zhang, Takehito Ouchi, Junjun Jing, Quan Yuan, Clifford J. Rosen, Chenchen Zhou
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Research Article Bone biology Development

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

Abstract

Regeneration of orofacial bone defects caused by inflammation-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 suppressed 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-deficient 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.

Authors

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

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Figure 1

PTH1R deletion causes decreased alveolar bone volume and PDL malformation.

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PTH1R deletion causes decreased alveolar bone volume and PDL malformatio...
(A–F) Immunofluorescence staining of PTH1R of Gli1CreER PTH1Rfl/+ Rosa26Ai14 and Gli1CreER PTH1Rfl/fl Rosa26Ai14 female mice at P42. (B, C, E, and F) Higher magnification of boxed regions, respectively. n = 3. (G) Three-dimensional micro-CT reconstruction of Gli1CreER PTH1Rfl/+ Rosa26Ai14 and Gli1CreER PTH1Rfl/fl Rosa26Ai14 mandibles at P42. n = 5 for male and n = 6 for female Gli1CreER PTH1Rfl/+ Rosa26Ai14 mice. n = 4 for male and n = 8 for female Gli1CreER PTH1Rfl/fl Rosa26Ai14 mice. (H) Quantitative micro-CT analysis of BV/TV, Tb.Th, Tb.Sp, and Tb.N of both sexes in each genotype. (I and L) HE staining of Gli1CreER PTH1Rfl/+ Rosa26Ai14 and Gli1CreER PTH1Rfl/fl Rosa26Ai14 female mice at P42. (J and M) Enlarged boxed areas of alveolar root furcation of mandibular first molar showed substantially reduced bone volume in PTH1R-cKO mice. (K and N) Higher magnification of PDL region showed the PDL space was replaced by bony tissue in PTH1R-cKO mice. n = 3. (O) Two-dimensional micro-CT images of coronal sections showed narrowed PDL space in PTH1R-cKO mice. n = 6. (P) Quantitative analysis of PDL width. n = 6. Female mice were used. (Q) Immunofluorescence staining of periostin (POSTN) of Gli1CreER PTH1Rfl/+ Rosa26Ai14 and Gli1CreER PTH1Rfl/fl Rosa26Ai14 female mice at P42. Boxed areas are shown at higher magnification. n = 3. Scale bar = 200 μm (A, B, I, and L), 50 μm (B, C, J, and K), 500 μm (G and O), and 100 μm (Q). Significance is determined using unpaired 2-sided Student’s t tests in H or using 2-way ANOVA with Tukey’s correction for multiple comparisons in D. Data are mean ± SEM. **P < 0.01, ****P < 0.0001.