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
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
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Research Article Bone biology Metabolism

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.

Authors

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

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Figure 1

HNF4A is expressed in bone and is reduced in humans and mice with CKD.

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HNF4A is expressed in bone and is reduced in humans and mice with CKD. (...
(A) Number of differentially regulated genes identified by RNA-Seq of bone biopsies from CKD patients with low–bone remodeling (LR) and high–bone remodeling (HR) renal osteodystrophy (ROD) versus healthy volunteers. (B–D) Heatmap-represented expression of genes identified in the topmost differentially regulated pathways in LR-ROD and HR-ROD bone biopsies versus healthy volunteers. n = 9 (Healthy and LR-ROD) and 11 (HR-ROD); corrected P < 0.05. Statistical analysis was performed with an ANOVA test followed by unpaired Student’s t test and corrected by the FDR. (E) Schematic representation of Hnf4α gene and different promoter P1– and P2–driven Hnf4α isoforms. (F–H) Comparative analysis of total Hnf4α mRNA in liver, kidney, and bone (F), Hnf4α isoforms 1 to 12 mRNA in bone (G), and Hnf4α isoforms 1 to 3 mRNA in bone of WT mice (H). (I) mRNA expression of Hnf4α1/2 in bone of WT and Col4a3KO mice with CKD. Values are expressed as the mean ± SEM. N = 5 per group. Corrected P < 0.05 versus aliver, bkidney, cHnf4α1–3, dHnf4α1, eHnf4α2, and *WT. Statistical analysis was performed with an unpaired Student’s t tests (I) or with an ANOVA followed by post hoc t tests to determine statistical differences and multiple-testing correction using the Holm-Bonferroni method (F–H).