title: RNA-binding protein Musashi2 induced by RANKL is critical for osteoclast survival.
abstract: The Musashi family of RNA-binding proteins, Musashi1 and Musashi2, regulate self-renewal and differentiation of neuronal and hematopoietic stem cells by modulating protein translation. It has been recently reported that Musashi2, not Musashi1, regulates hematopoietic stem cells. Although osteoclasts are derived from hematopoietic cells, the expression and functions of Musashi proteins in osteoclast lineage cells remain unknown. In this study, we have uncovered that Musashi2 is the predominant isoform of Musashi proteins in osteoclast precursors and its expression is upregulated by receptor activator of NF-κB ligand (RANKL) during osteoclast differentiation. Knocking down the expression of Musashi2 in osteoclast lineage cells by shRNAs attenuates nuclear factor of activated T cells 1 (NFATc1) expression and osteoclast formation in vitro. Mechanistically, loss of Musashi2 inhibits Notch signaling during osteoclast differentiation and induces apoptosis in pre-osteoclasts. In contrast, depletion of Musashi2 has no effects on cell cycle progression and p21(WAF-1) protein expression in macrophages. Furthermore, depletion of Notch2 and its downstream target Hes1 in osteoclast precursors by shRNAs abrogates osteoclastogenesis by inhibiting NFATc1. Finally, absence of Musashi2 in osteoclast precursors promotes apoptosis and inhibits RANKL-induced nuclear factor-κB (NF-κB) activation, which is essential for osteoclast survival, Thus, Musashi2 is required for cell survival and optimal osteoclastogenesis by affecting Notch signaling and NF-κB activation.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ye
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D061251:Primary Cell Culture; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489734:Hes1 protein, mouse; C104786:Msi1h protein, mouse; C499059:Msi2h protein, mouse; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse; C497765:Notch2 protein, mouse; D053245:RANK Ligand; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051883:Receptor, Notch2; C505689:Tnfsf11 protein, mouse; D000072056:Transcription Factor HES-1