title: MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation.
abstract: Transcription factors NFATc1, PU.1, and MITF collaborate to regulate specific genes in response to colony-stimulating factor-1 (CSF-1) and receptor activator of NF-kappaB ligand (RANKL) signaling during osteoclast differentiation. However, molecular details concerning timing and mechanism of specific events remain ill-defined. In bone marrow-derived precursors, CSF-1 alone promoted assembly of MITF-PU.1 complexes at osteoclast target gene promoters like cathepsin K and acid 5 phosphatase without increasing gene expression. The combination of RANKL and CSF-1 concurrently increased the levels of MAPK-phosphorylated forms of MITF, p38 MAPK, and SWI/SNF chromatin-remodeling complexes bound to these target promoters and markedly increased expression of the genes. NFATc1 was subsequently recruited to complexes at the promoters during terminal stages of osteoclast differentiation. Genetic analysis of Mitf and Pu.1 in mouse models supported the critical interaction of these genes in osteoclast differentiation. The results define MITF and PU.1 as nuclear effectors that integrate CSF-1/RANKL signals during osteoclast differentiation to initiate expression of target genes, whereas a complex that includes NFATc1 may act to maintain target gene expression in differentiated cells.
authors.affiliation: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sudarshana M
authors.initials: SM
authors.lastname: Sharma
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronisz
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Krupen
authors.initials: K
authors.lastname: Patel
authors.forename: Kim C
authors.initials: KC
authors.lastname: Mansky
authors.forename: Said
authors.initials: S
authors.lastname: Sif
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
mesh_terms: D000135:Acid Phosphatase / Q000096:biosynthesis; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D051739:Microphthalmia-Associated Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071681:Tartrate-Resistant Acid Phosphatase; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000135:Acid Phosphatase; D056657:Cathepsin K; D002403:Cathepsins; D002868:Chromosomal Proteins, Non-Histone; D007527:Isoenzymes; D016173:Macrophage Colony-Stimulating Factor; D051739:Microphthalmia-Associated Transcription Factor; D050778:NFATC Transcription Factors; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D000071681:Tartrate-Resistant Acid Phosphatase; D015534:Trans-Activators; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099232:Proto-Oncogene Protein Spi-1; C497235:Mitf protein, mouse; C494005:Nfatc1 protein, mouse; C445179:SWI-SNF-B chromatin-remodeling complex; C505689:Tnfsf11 protein, mouse; C534132:Ctsk protein, mouse