Defective co-activator recruitment in osteoclasts from microphthalmia-oak ridge mutant mice.
The three basic DNA-binding domain mutations of the microphthalmia-associated transcription factor (Mitf), Mitf(mi/mi), Mitf(or/or), and Mitf(wh/wh) affect osteoclast differentiation with variable penetrance while completely impairing melanocyte development. Mitf(or/or) mice exhibit osteopetrosis that improves with age and their osteoclasts form functional multinuclear osteoclasts, raising the question as to why the Mitf(or/or) mutation results in osteopetrosis. Here we show that Mitf(or/or) osteoclasts express normal levels of acid phosphatase 5 (Acp5) mRNA and significantly lower levels of Cathepsin K (Ctsk) mRNA during receptor activator of nuclear factor kappa B (NFkappaB) ligand (RANKL)-mediated differentiation. Studies using chromatin immunoprecipitation (ChIP) analysis indicate that low levels of Mitf(or/or) protein are recruited to the Ctsk promoter. However, enrichment of Mitf-transcriptional co-activators PU.1 and Brahma-related gene 1 (Brg1) are severely impaired at the Ctsk promoter of Mitf(or/or) osteoclast precursors, indicating that defective recruitment of co-activators by the mutant Mitf(or/or) results in impaired Ctsk expression in osteoclasts. Cathepsin K may thus represent a unique class of Mitf-regulated osteoclast-specific genes that are important for osteoclast function.
Sharma
Sudarshana M
SM
Department of Molecular and Cellular Biochemistry, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Sif
Said
S
Ostrowski
Michael C
MC
Sankar
Uma
U
D000135:Acid Phosphatase / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004265:DNA Helicases / Q000378:metabolism*; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D000135:Acid Phosphatase; D056657:Cathepsin K; D002403:Cathepsins; D004265:DNA Helicases; D007527:Isoenzymes; D051739:Microphthalmia-Associated Transcription Factor; D016328:NF-kappa B; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D000071681:Tartrate-Resistant Acid Phosphatase; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C497235:Mitf protein, mouse; C505689:Tnfsf11 protein, mouse; C000605511:Acp5 protein, mouse; C534132:Ctsk protein, mouse; C513194:Smarca4 protein, mouse