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 4

Gli1CreER PTH1Rfl/fl mice exhibit restricted periapical lesion because of activated bone turnover.

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Gli1CreER PTH1Rfl/fl mice exhibit restricted periapical lesion because ...
(A) Two-dimensional micro-CT images of the mandibles from Gli1CreER PTH1Rfl/+ Rosa26Ai14 and Gli1CreER PTH1Rfl/fl Rosa26Ai14 mice in sham and AP groups. Red arrowheads depict the region of periapical lesion. n = 6 for sham and n = 5 for AP of Gli1CreER PTH1Rfl/+ Rosa26Ai14 mice. n = 6 for sham and n = 7 for AP of Gli1CreER PTH1Rfl/fl Rosa26Ai14 mice. (B) Quantitative analysis of trabecular bone parameters including BV/TV (%), Tb.Sp (mm), and Tb.Th (mm). (C) HE staining of the distal root of mandibular first molar showed the periapical lesion induced by AP. n = 3. (D and E) TRAP staining and quantification of TRAP+ cells/bone surface. n = 5. (F and G) Immunofluorescence staining and quantification showed increasing Runx2+Gli1+ cell numbers in periapical bone of Gli1CreER PTH1Rfl/fl Rosa26Ai14 mice under both homeostasis and AP conditions. Yellow dashed lines depict the region of distal root of the mandibular first molar. Boxed areas are shown at higher magnification. n = 4. (H and I) Immunofluorescence staining and quantification showed increased Sp7+Gli1+ cell numbers in inflammatory periapical bone of Gli1CreER PTH1Rfl/fl Rosa26Ai14 mice. Yellow dashed lines depict the region of distal root of the mandibular first molar. Boxed areas are shown at higher magnification. n = 4. Scale bar = 500 μm (A) and 100 μm (C, D, F, and H). Data were all obtained in male mice. Significance is determined using 2-way ANOVA with Tukey’s correction for multiple comparisons. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.