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 2

HNF4α2 is a major regulator of osteogenesis and metabolism in osteoblasts.

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HNF4α2 is a major regulator of osteogenesis and metabolism in osteoblast...
(A and B) Hnf4α1/2 mRNA expression in differentiated primary bone marrow stromal cells (BMSCs), mature osteoblasts (OBs), and MC3T3-E1 osteoblasts (A), and in MC3T3-E1 osteoblasts transfected with an empty vector (Ctr), Hnf4α1 (Hnf4α1Tg), and Hnf4α2 (Hnf4α2Tg) expression transgene (B). (C and D) mRNA expression of markers of osteoblast differentiation Runx2 and Sp7. Values are expressed as the mean ± SEM. n ≥ 3 per group of a representative experiment performed at least 3 times; corrected P < 0.05 versus *BMSC or Ctr. Statistical analysis was performed with an ANOVA test followed by post hoc t tests to determine statistical differences and multiple-testing correction using the Holm-Bonferroni method. (E) Number of differentially regulated genes identified by RNA-Seq in Hnf4α1Tg and Hnf4α2Tg osteoblasts versus Ctr. (F) Canonical pathway analysis and prediction of pathway activation of differentially regulated genes identified by RNA-Seq of Ctr, Hnf4α1Tg, and Hnf4α2Tg osteoblasts. (G and H) Heatmap-represented expression of genes modified and involved in osteogenesis and metabolism pathways in Ctr, Hnf4α1Tg, and Hnf4α2Tg osteoblasts. Corrected P < 0.05; n = 3 per group. Statistical analysis was performed with an unpaired Student’s t test and corrected by the FDR.