title: Immediate effects of retinoic acid on gene expression in primary murine osteoblasts.
abstract: Consistent with clinical observations demonstrating that hypervitaminosis A is associated with increased skeletal fracture risk, we have previously found that dietary retinol deprivation partially corrects the bone mineralization defects in a mouse model of X-linked hypophosphatemic rickets. That retinol-dependent signaling pathways impact the skeleton is further supported by various findings demonstrating a negative influence of retinoic acid (RA) on bone-forming osteoblasts. We hypothesized that RA would directly regulate the expression of specific target genes in osteoblasts, and we aimed to identify these by genome-wide expression analyses. Here we show that high dietary retinol intake in mice causes low bone mass associated with increased osteoclastogenesis and decreased osteoblastogenesis, but intact bone matrix mineralization. We additionally found that short-term treatment of primary osteoblasts with RA causes a rapid induction of specific genes involved in either retinol-dependent signaling (i.e. Rara, Crabp2) or skeletal remodeling (i.e. Twist2, Tnfsf11). In contrast, neither expression of established osteoblast differentiation markers nor the proliferation rate was immediately affected by RA administration. Collectively, our data suggest that the negative effects of vitamin A on skeletal integrity are explainable by an immediate influence of RA signaling on specific genes in osteoblasts that in turn influence bone remodeling.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Timur A
authors.initials: TA
authors.lastname: Yorgan
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Heckt
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rendenbach
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Helmis
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seitz
authors.affiliation: Department of Clinical Chemistry, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany. schinke@uke.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013194:Staining and Labeling; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D014212:Tretinoin
keywords: Osteoblast; Retinoic acid; Twist2; Vitamin A