title: miRNA-34c regulates Notch signaling during bone development.
abstract: During bone homeostasis, osteoblast and osteoclast differentiation is coupled and regulated by multiple signaling pathways and their downstream transcription factors. Here, we show that microRNA 34 (miR-34) is significantly induced by BMP2 during osteoblast differentiation. In vivo, osteoblast-specific gain of miR-34c in mice leads to an age-dependent osteoporosis due to the defective mineralization and proliferation of osteoblasts and increased osteoclastogenesis. In osteoblasts, miR-34c targets multiple components of the Notch signaling pathway, including Notch1, Notch2 and Jag1 in a direct manner, and influences osteoclast differentiation in a non-cell-autonomous fashion. Taken together, our results demonstrate that miR-34c is critical during osteoblastogenesis in part by regulating Notch signaling in bone homeostasis. Furthermore, miR-34c-mediated post-transcriptional regulation of Notch signaling in osteoblasts is one possible mechanism to modulate the proliferative effect of Notch in the committed osteoblast progenitors which may be important in the pathogenesis of osteosarcomas. Therefore, understanding the functional interaction of miR-34 and Notch signaling in normal bone development and in bone cancer could potentially lead to therapies modulating miR-34 signaling.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine,One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Yangjin
authors.initials: Y
authors.lastname: Bae
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Huan-Chang
authors.initials: HC
authors.lastname: Zeng
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.forename: Brian C
authors.initials: BC
authors.lastname: Dawson
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.forename: Jianning
authors.initials: J
authors.lastname: Tao
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology; D010012:Osteogenesis; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; C551848:MIRN34a microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins