Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPMARTINEZ-CALLE, MartaCOURBON, GuillaumeHUNT-TOBEY, BridgetFRANCIS, ConnorSPINDLER, JadeahWANG, XueyanREIS, Luciene M. dosMARTINS, Carolina S. W.SALUSKY, Isidro B.MALLUCHE, HartmutNICKOLAS, Thomas L.MOYSES, Rosa M. A.DAVID, ValentinMARTIN, Aline2023-08-162023-08-162023JOURNAL OF CLINICAL INVESTIGATION, v.133, n.11, article ID e159928, 18p, 20230021-9738https://observatorio.fm.usp.br/handle/OPI/54820Renal 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 4 & alpha; (HNF4 & alpha;), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4 & alpha; expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4 & alpha; resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4 & alpha;1 and Hnf4 & alpha;2, we showed that HNF4 & alpha;2 is the main osseous Hnf4 & alpha; isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4 & alpha;2 prevented bone loss in mice with CKD. Our results showed that HNF4 & alpha;2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.engopenAccessnuclear factor 4-alphagenome-wide associationchronic kidney-diseasegene-expressionmouse modelhip fracturep1 promoterliverisoformsmetabolismarticleCopyright AMER SOC CLINICAL INVESTIGATION INC10.1172/JCI159928Medicine, Research & Experimental1558-8238