title: Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha.
abstract: In response to various stresses including viral infection, nutrient deprivation, and stress to the endoplasmic reticulum, eukaryotic translation initiation factor 2 alpha (eIF2α) is phosphorylated to cope with stress induced apoptosis. Although bone cells are sensitive to environmental stresses that alter the phosphorylation level of eIF2α, little is known about the role of eIF2α mediated signaling during the development of bone-resorbing osteoclasts. Using two chemical agents (salubrinal and guanabenz) that selectively inhibit de-phosphorylation of eIF2α, we evaluated the effects of phosphorylation of eIF2α on osteoclastogenesis of RAW264.7 pre-osteoclasts as well as development of MC3T3 E1 osteoblast-like cells. The result showed that salubrinal and guanabenz stimulated matrix deposition of osteoblasts through upregulation of activating transcription factor 4 (ATF4). The result also revealed that these agents reduced expression of the nuclear factor of activated T cells c1 (NFATc1) and inhibited differentiation of RAW264.7 cells to multi-nucleated osteoclasts. Partial silencing of eIF2α with RNA interference reduced suppression of salubrinal/guanabenz-driven downregulation of NFATc1. Collectively, we demonstrated that the elevated phosphorylation level of eIF2α not only stimulates osteoblastogenesis but also inhibit osteoclastogenesis through regulation of ATF4 and NFATc1. The results suggest that eIF2α-mediated signaling might provide a novel therapeutic target for preventing bone loss in osteoporosis.
authors.affiliation: Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, SL155, 723 West Michigan Street, Indianapolis, IN, 46202, USA, hamamurk@iupui.edu.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hamamura
authors.forename: Nancy
authors.initials: N
authors.lastname: Tanjung
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D016762:Genes, fos / Q000235:genetics; D006143:Guanabenz / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D000071681:Tartrate-Resistant Acid Phosphatase; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C081452:Atf4 protein, mouse; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C450519:Oscar protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C496827:salubrinal; D015675:Osteocalcin; D051701:Activating Transcription Factor 4; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D006143:Guanabenz; D013890:Thiourea
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