PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner
Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis, and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate toward...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83345 |
| _version_ | 1797829713503191040 |
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| author | Hanghang Liu Akane Wada Isabella Le Phuong T Le Andrew WF Lee Jun Zhou Francesca Gori Roland Baron Clifford J Rosen |
| author_facet | Hanghang Liu Akane Wada Isabella Le Phuong T Le Andrew WF Lee Jun Zhou Francesca Gori Roland Baron Clifford J Rosen |
| author_sort | Hanghang Liu |
| collection | DOAJ |
| description | Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis, and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate toward osteogenesis and higher bone mass. PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of Zfp467 in osteogenic precursors would lead to high bone mass in mice. Prrx1Cre; Zfp467fl/fl but not AdipoqCre; Zfp467fl/fl mice exhibit high bone mass and greater osteogenic differentiation similar to the Zfp467-/- mice. qPCR results revealed that PTH suppressed Zfp467 expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of Zfp467 and gene silencing of Pth1r caused an increase in Zfp467 mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of Zfp467 resulted in higher nuclear translocation of NFκB1 that binds to the P2 promoter of the Pth1r and increased its transcription. As expected, Zfp467-/- cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in Zfp467-/- COBs, and the pro-osteogenic effect of Zfp467 deletion was blocked by gene silencing of Pth1r or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of Zfp467 results in a pathway that increases Pth1r transcription via NFκB1 and thus cellular responsiveness to PTH/PTHrP, ultimately leading to enhanced bone formation. |
| first_indexed | 2024-04-09T13:25:43Z |
| format | Article |
| id | doaj.art-c5eaaa87888740f09a5442e0391081b9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T13:25:43Z |
| publishDate | 2023-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c5eaaa87888740f09a5442e0391081b92023-05-10T13:22:48ZengeLife Sciences Publications LtdeLife2050-084X2023-04-011210.7554/eLife.83345PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent mannerHanghang Liu0Akane Wada1Isabella Le2Phuong T Le3Andrew WF Lee4Jun Zhou5Francesca Gori6https://orcid.org/0000-0001-5685-8303Roland Baron7Clifford J Rosen8https://orcid.org/0000-0003-3436-8199Maine Medical Center Research Institute, Maine Medical Center, Scarborough, United States; West China Hospital of Stomatology, Sichuan University, Sichuan, ChinaDivision of Bone and Mineral Research, Dept of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, United States; Harvard Medical School, Department of Medicine and Endocrine Unit, Massachusetts General Hospital, Boston, United StatesMaine Medical Center Research Institute, Maine Medical Center, Scarborough, United States; Graduate Medical Sciences, Boston University School of Medicine, Boston, United StatesMaine Medical Center Research Institute, Maine Medical Center, Scarborough, United StatesMaine Medical Center Research Institute, Maine Medical Center, Scarborough, United States; University of New England, College of Osteopathic Medicine, Biddeford, United StatesDivision of Bone and Mineral Research, Dept of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, United States; Harvard Medical School, Department of Medicine and Endocrine Unit, Massachusetts General Hospital, Boston, United StatesDivision of Bone and Mineral Research, Dept of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, United StatesDivision of Bone and Mineral Research, Dept of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, United States; Harvard Medical School, Department of Medicine and Endocrine Unit, Massachusetts General Hospital, Boston, United StatesMaine Medical Center Research Institute, Maine Medical Center, Scarborough, United StatesConditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis, and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate toward osteogenesis and higher bone mass. PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of Zfp467 in osteogenic precursors would lead to high bone mass in mice. Prrx1Cre; Zfp467fl/fl but not AdipoqCre; Zfp467fl/fl mice exhibit high bone mass and greater osteogenic differentiation similar to the Zfp467-/- mice. qPCR results revealed that PTH suppressed Zfp467 expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of Zfp467 and gene silencing of Pth1r caused an increase in Zfp467 mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of Zfp467 resulted in higher nuclear translocation of NFκB1 that binds to the P2 promoter of the Pth1r and increased its transcription. As expected, Zfp467-/- cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in Zfp467-/- COBs, and the pro-osteogenic effect of Zfp467 deletion was blocked by gene silencing of Pth1r or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of Zfp467 results in a pathway that increases Pth1r transcription via NFκB1 and thus cellular responsiveness to PTH/PTHrP, ultimately leading to enhanced bone formation.https://elifesciences.org/articles/83345zinc finger protein 467PTH receptorPTHPKA pathwayosteogenesis |
| spellingShingle | Hanghang Liu Akane Wada Isabella Le Phuong T Le Andrew WF Lee Jun Zhou Francesca Gori Roland Baron Clifford J Rosen PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner eLife zinc finger protein 467 PTH receptor PTH PKA pathway osteogenesis |
| title | PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner |
| title_full | PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner |
| title_fullStr | PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner |
| title_full_unstemmed | PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner |
| title_short | PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner |
| title_sort | pth regulates osteogenesis and suppresses adipogenesis through zfp467 in a feed forward pth1r cyclic amp dependent manner |
| topic | zinc finger protein 467 PTH receptor PTH PKA pathway osteogenesis |
| url | https://elifesciences.org/articles/83345 |
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