title: PTH regulates myleoid ELF-1-like factor (MEF)-induced MAB-21-like-1 (MAB21L1) expression through the JNK1 pathway.
abstract: Continuous treatment with parathyroid hormone (PTH) or excess endogenous PTH due to primary hyperparathyroidism causes increased bone resorption and, subsequently, decreased bone volume. Our previous studies showed that myeloid Elf-1-like factor (MEF) not only suppresses osteoblast differentiation through inhibition of Runx2 activity and other osteogenesis-related genes but also specifically increases the expression of Mab21, a potential transcriptional repressor of osteoblast differentiation. Here we show that the JNK1 pathway is involved in the MEF-mediated up-regulation of Mab21 expression due to PTH stimulation. PTH increased the transcription level of Mab21 in MG63 human osteoblastic cells, in contrast to the suppressive effect of TGFβ1. PTH phosphorylates serine residues of MEF as well as c-Jun, a known substrate of JNK1. By in vitro kinase assay, we confirmed that MEF is phosphorylated by JNK1, but not by ERK. Co-transfection of MEF with both MKK4 and JNK1 increased the promoter activity of Mab21 in CV1 cells significantly more than MEF alone. We also identified the phosphorylation of MEF serine 641 by in vitro and in vivo JNK1 kinase assays combined with a proteomics approach. In conclusion, our findings indicate that MEF is involved in PTH suppression of osteoblasts through activating the MKK4/JNK1 pathway and subsequently up-regulating Mab21 expression.
authors.affiliation: Department of Biochemistry, School of Dentistry, Kyungpook National University, Korea.
authors.forename: Byung-Gyu
authors.initials: BG
authors.lastname: Kim
authors.forename: Youn-Je
authors.initials: YJ
authors.lastname: Park
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Je-Yoel
authors.initials: JY
authors.lastname: Cho
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; D018398:Homeodomain Proteins; C499231:MAB21L1 protein, human; D010281:Parathyroid Hormone; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D048055:Mitogen-Activated Protein Kinase 8; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human