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 8

Bone Hnf4α expression is reduced in mice with CKD and in response to acute and chronic inflammation.

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Bone Hnf4α expression is reduced in mice with CKD and in response to acu...
(A) Renal function in 20-week-old sham-operated and bilateral ischemia/reperfusion injury (bIRI) WT male mice assessed by measurements of blood urea nitrogen (BUN). (B) Bone Hnf4α expression levels in 20-week-old sham and bIRI male mice. (C–H) Microtomography analysis of femur metaphysis secondary spongiosa (C–E) and femur cortical bone at metaphysis (F–H) in 20-week-old WT sham and bIRI mice. Ct, cortical; Po, porosity. Values are expressed as the mean ± SEM. n ≥ 4 per group; P < 0.05 versus *sham. (I and J) Hnf4α mRNA expression in a representative experiment performed at least 3 times in differentiated primary BMSC cultures isolated from WT mice treated for 6 hours with different concentrations of IL-1β, PTH, inorganic phosphate salts, IL-6, or TNF-α. (K and L) mRNA expression of bone Hnf4α in tibiae from WT mice injected with saline (Ctr), IL-1β, or heat-killed Brucella abortus (BA) 6 hours (K) or 14 days (L) after injection. Values are expressed as the mean ± SEM. n ≥ 4 per group; corrected P < 0.05 versus *Ctr. Statistical analysis was performed with an unpaired Student’s t test (A–H and L) or with an ANOVA followed by post hoc t tests and multiple-testing correction using the Holm-Bonferroni method (I–K).