title: GATA4 is essential for bone mineralization via ERα and TGFβ/BMP pathways.
abstract: Osteoporosis is a disease characterized by low bone mass, leading to an increased risk of fragility fractures. GATA4 is a zinc-finger transcription factor that is important in several tissues, such as the heart and intestines, and has recently been shown to be a pioneer factor for estrogen receptor alpha (ERα) in osteoblast-like cells. Herein, we demonstrate that GATA4 is necessary for estrogen-mediated transcription and estrogen-independent mineralization in vitro. In vivo deletion of GATA4, driven by Cre-recombinase in osteoblasts, results in perinatal lethality, decreased trabecular bone properties, and abnormal bone development. Microarray analysis revealed GATA4 suppression of TGFβ signaling, necessary for osteoblast progenitor maintenance, and concomitant activation of BMP signaling, necessary for mineralization. Indeed, pSMAD1/5/8 signaling, downstream of BMP signaling, is decreased in the trabecular region of conditional knockout femurs, and pSMAD2/3, downstream of TGFβ signaling, is increased in the same region. Together, these experiments demonstrate the necessity of GATA4 in osteoblasts. Understanding the role of GATA4 to regulate the tissue specificity of estrogen-mediated osteoblast gene regulation and estrogen-independent bone differentiation may help to develop therapies for postmenopausal osteoporosis.
authors.affiliation: University of California, Los Angeles (UCLA)/Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Güemes
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Garcia
authors.forename: Diana
authors.initials: D
authors.lastname: Rigueur
authors.forename: Stephanie
authors.initials: S
authors.lastname: Runke
authors.forename: Weiguang
authors.initials: W
authors.lastname: Wang
authors.forename: Gexin
authors.initials: G
authors.lastname: Zhao
authors.forename: Victor Hugo
authors.initials: VH
authors.lastname: Mayorga
authors.forename: Elisa
authors.initials: E
authors.lastname: Atti
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
authors.forename: Bruno
authors.initials: B
authors.lastname: Péault
authors.forename: Karen
authors.initials: K
authors.lastname: Lyons
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Miranda-Carboni
authors.forename: Susan A
authors.initials: SA
authors.lastname: Krum
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D047628:Estrogen Receptor alpha; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: ESTROGEN; GATA4; TGF BETA, BMP, OSTEOBLAST