Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy

Marta Martinez-Calle; Guillaume Courbon; Bridget Hunt-Tobey; Connor Francis; Jadeah Spindler; Xueyan Wang; Luciene M. dos Reis; Carolina S.W. Martins; Isidro B. Salusky; Hartmut Malluche; Thomas L. Nickolas; Rosa M.A. Moyses; Aline Martin; Valentin David

doi:10.1172/JCI159928

Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy

Marta Martinez-Calle, Guillaume Courbon, Bridget Hunt-Tobey, Connor Francis, Jadeah Spindler, Xueyan Wang, Luciene M. dos Reis, Carolina S.W. Martins, Isidro B. Salusky, Hartmut Malluche, Thomas L. Nickolas, Rosa M.A. Moyses, Aline Martin, Valentin David^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.

Original language	English (US)
Article number	e159928
Journal	Journal of Clinical Investigation
Volume	133
Issue number	11
DOIs	https://doi.org/10.1172/JCI159928
State	Published - Jun 1 2023

Funding

This study was supported by grants from the National Institutes of Health, to VD (R01DK102815, R01DK114158, R01DK132657), to AM (R01DK101730, R01DK131046), and to TLN, IBS, HM, and VD (R56DK127986). This study used services from the Metabo-lomics Core Facility at Robert H. Lurie Comprehensive Cancer Center, the NUseq Core, and core services from the Northwestern University George M. O’Brien Kidney Research Core Center (NU GoKidney), an NIH/NIDDK–funded program (P30DK114857). Conflict of interest: VD has received research funding from Akebia and from Vifor Pharma and consulting honoraria from Keryx Biopharmaceuticals, Vifor Pharma, Luitpold, and Amgen outside of the submitted work. TLN has had consultancy agreements with Pharmacosmos and has received research funding from Amgen and consulting honoraria from Amgen and Pharmacosmos outside of the submitted work. RMAM has received lecture honoraria from Amgen and Accord outside of the submitted work. IBS has received honoraria from Akebia, Inozyme, Ultragenyx, Amgen, and Abbvie outside of the submitted work. Copyright: © 2023, Martinez-Calle et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: March 4, 2022; Accepted: April 17, 2023; Published: June 1, 2023. Reference information: J Clin Invest. 2023;133(11):e159928. https://doi.org/10.1172/JCI159928. This study was supported by grants from the National Institutes of Health, to VD (R01DK102815, R01DK114158, R01DK132657), to AM (R01DK101730, R01DK131046), and to TLN, IBS, HM, and VD (R56DK127986). This study used services from the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center, the NUseq Core, and core services from the Northwestern University George M. O'Brien Kidney Research Core Center (NU GoKidney), an NIH/NIDDK-funded program (P30DK114857).

ASJC Scopus subject areas

General Medicine

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10.1172/JCI159928

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Martinez-Calle, M., Courbon, G., Hunt-Tobey, B., Francis, C., Spindler, J., Wang, X., dos Reis, L. M., Martins, C. S. W., Salusky, I. B., Malluche, H., Nickolas, T. L., Moyses, R. M. A., Martin, A., & David, V. (2023). Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy. Journal of Clinical Investigation, 133(11), Article e159928. https://doi.org/10.1172/JCI159928

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title = "Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy",

abstract = "Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.",

author = "Marta Martinez-Calle and Guillaume Courbon and Bridget Hunt-Tobey and Connor Francis and Jadeah Spindler and Xueyan Wang and {dos Reis}, {Luciene M.} and Martins, {Carolina S.W.} and Salusky, {Isidro B.} and Hartmut Malluche and Nickolas, {Thomas L.} and Moyses, {Rosa M.A.} and Aline Martin and Valentin David",

note = "Publisher Copyright: Copyright: {\textcopyright} 2023, Martinez-Calle et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2023",

month = jun,

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doi = "10.1172/JCI159928",

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Martinez-Calle, M, Courbon, G, Hunt-Tobey, B, Francis, C, Spindler, J, Wang, X, dos Reis, LM, Martins, CSW, Salusky, IB, Malluche, H, Nickolas, TL, Moyses, RMA, Martin, A & David, V 2023, 'Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy', Journal of Clinical Investigation, vol. 133, no. 11, e159928. https://doi.org/10.1172/JCI159928

TY - JOUR

T1 - Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy

AU - Martinez-Calle, Marta

AU - Courbon, Guillaume

AU - Hunt-Tobey, Bridget

AU - Francis, Connor

AU - Spindler, Jadeah

AU - Wang, Xueyan

AU - dos Reis, Luciene M.

AU - Martins, Carolina S.W.

AU - Salusky, Isidro B.

AU - Malluche, Hartmut

AU - Nickolas, Thomas L.

AU - Moyses, Rosa M.A.

AU - Martin, Aline

AU - David, Valentin

PY - 2023/6/1

Y1 - 2023/6/1

N2 - Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.

AB - Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.

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ER -

Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy

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