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Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy
Marta Martinez-Calle1, Guillaume Courbon1, Bridget Hunt-Tobey1
1Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
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.
Insights
Hepatocyte nuclear factor 4α (HNF4α), a protein usually in the liver, is crucial for bone health. Reduced HNF4α in chronic kidney disease patients contributes to bone disorder, but HNF4α2 can prevent bone loss.
Area of Science:
- Bone biology and metabolism
- Endocrinology and transcriptional regulation
Background:
- Renal osteodystrophy (ROD) is a common complication of chronic kidney disease (CKD), leading to fractures and cardiovascular issues.
- Hepatocyte nuclear factor 4α (HNF4α), a key liver transcription factor, has an uncharacterized role in bone metabolism.
Purpose of the Study:
- To investigate the role of HNF4α in bone metabolism and its involvement in the pathogenesis of ROD.
- To identify the specific HNF4α isoform regulating osteogenesis in bone.
Main Methods:
- Analysis of HNF4α expression in bone from patients with ROD and mouse models.
- Generation of mice with osteoblast-specific deletion or overexpression of Hnf4α.
- Multi-omics analyses (genomics, transcriptomics, proteomics) of bone and cells.
- Assessment of osteogenesis, cell metabolism, and cell death.
Main Results:
- HNF4α is expressed in bone and significantly reduced in ROD.
- Osteoblast-specific Hnf4α deletion impairs osteogenesis in vitro and in vivo.
- HNF4α2 is identified as the primary osseous isoform regulating osteogenesis, metabolism, and cell death.
- Overexpression of HNF4α2 in osteoblasts prevents bone loss in a CKD mouse model.
Conclusions:
- HNF4α2 is a critical transcriptional regulator of osteogenesis in bone.
- HNF4α2 plays a protective role against bone loss in the context of CKD and ROD.
- Targeting HNF4α2 may offer a therapeutic strategy for managing renal osteodystrophy.
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