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
N1 - Publisher Copyright:
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.
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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U2 - 10.1172/JCI159928
DO - 10.1172/JCI159928
M3 - Article
C2 - 37079387
AN - SCOPUS:85160966549
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
M1 - e159928
ER -