Identification of an osteoclast transcription factor that binds to the human T cell leukemia virus type I-long terminal repeat enhancer element.
Transgenic mice expressing human T cell leukemia virus type I (HTLV-I)-tax under the control of HTLV-I-long terminal repeat (LTR) promoter develop skeletal abnormalities with high bone turnover and myelofibrosis. In these animals, Tax is highly expressed in bone with a pattern of expression restricted to osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. To test the hypothesis that lineage-specific transcription factors promote transgene expression from the HTLV-I-LTR in osteoclasts, we first examined tax expression in transgenic bone marrow cultures. Expression was dependent on 1alpha,25-dihydroxycholecalciferol and coincided with tartrate-resistant acid phosphatase (TRAP) expression, a marker of osteoclast differentiation. Furthermore, Tax was expressed in vitronectin receptor-positive mononuclear precursors as well as in mature osteoclast-like cells (OCLs). Consistent with our hypothesis, electrophoretic mobility shift assays revealed the presence of an OCL nuclear factor (NFOC-1) that binds to the LTR 21-base pair direct repeat, a region critical for the promoter activity. This binding is further enhanced by Tax. Since NFOC-1 is absent in macrophages and conserved in osteoclasts among species including human, such a factor may play a role in lineage determination and/or in expression of the differentiated osteoclast phenotype.
Inoue
D
D
Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Santiago
P
P
Horne
W C
WC
Baron
R
R
D000135:Acid Phosphatase / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation; D004279:DNA, Viral / Q000737:chemistry / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000096:biosynthesis* / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D015345:Oligonucleotide Probes; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*
D004279:DNA, Viral; D016356:Gene Products, tax; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D014157:Transcription Factors; D000135:Acid Phosphatase; D002117:Calcitriol