The microphthalmia transcription factor (MITF) is required for terminal differentiation of developmentally unrelated cell types including osteoclasts, mast cells, pigmented retinal epithelial cells and melanocytes and regulates distinct target genes in each of these cell types. During terminal differentiation of osteoclasts, MITF regulates a set of genes that are required for bone resorption, including Cathepsin K (Ctsk), the chloride channel Ccln7, Ostm1/grey lethal, and tartrate resistant acid phosphatase/acid phosphatase 5 (Trap/Acp5). Mutations in this set of genes are associated with osteoclast dysfunction and bone disorders in humans and mice, strongly arguing that MITF plays a central role in gene regulation during terminal osteoclast differentiation. Our work has demonstrated that interactions between MITF and the ETS-family factor PU.1 are necessary to selectively regulate this set of target genes in osteoclasts. MITF is also a direct target of CSF-1/RANKL signaling during osteoclast differentiation, activated directly by Mitogen Activated Protein Kinases (MAPK), Erk and p38. In the current grant period, our work has revealed interacting proteins that suggest potential mechanisms underlying ITF/PU.1 action in osteoclasts. Unexpectedly, in committed osteoclast progenitors treated with CSF-1 alone, the MITF/PU.1 complex interacts with the repressor Eos and co-repressor complexes to suppress the expression of osteoclast target genes. In the presence of both CSF-1 and RANKL, the Eos/co-repressor complexes are replaced by complexes that contain p38 MAPK, the co-activator CBP/p300, and the BRG-1 chromatin remodeling complex. Subsequent to these events, the transcription factor NFATc1 is recruited to the target promoters. This data leads to our overall hypothesis: MITF/PU.1 complexes act in committed myeloid progenitors as integrators of signals encountered in the bone microenvironment to effect changes in the expression of genes essential for osteoclast function.

Public Health Relevance

This work will define mechanisms by which gene expression patterns are regulated in committed myeloid progenitors before signals from the bone microenvironment trigger differentiation into specific cell types. This is a key problem not only in osteoclast differentiation, but is a problem of general biological interest. In addition, these studies may have direct applications to significant human diseases. In particular, osteoporosis in post-menopausal women and the osteolytic bone destruction that occurs in patients with multiple myeloma, breast cancer and prostate cancer are examples of clinical conditions where this research may have potential impact. The identification of molecular targets in cancer cells and the development of pharmacological agents that selectively interfere with the action of these targets have been long term goals in cancer research that have finally started to pay dividends. A similar strategy in bone diseases should allow for the rational design of agents that interfere with specific molecular targets. The genetics and molecular biology of MITF suggests that the MITF pathway may provide molecular targets for certain bone disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Chen, Faye H
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Ohio State University
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Carey, Heather A; Hildreth 3rd, Blake E; Geisler, Jennifer A et al. (2018) Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation. Bone Res 6:8
Hawley, Catherine A; Rojo, Rocio; Raper, Anna et al. (2018) Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System. J Immunol 200:2209-2223
Peterson, Jennifer M; Wang, David J; Shettigar, Vikram et al. (2018) NF-?B inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model. Nat Commun 9:3431
Carey, Heather A; Bronisz, Agnieszka; Cabrera, Jennifer et al. (2016) Failure to Target RANKL Signaling Through p38-MAPK Results in Defective Osteoclastogenesis in the Microphthalmia Cloudy-Eyed Mutant. J Cell Physiol 231:630-40
Bronisz, Agnieszka; Carey, Heather A; Godlewski, Jakub et al. (2014) The multifunctional protein fused in sarcoma (FUS) is a coactivator of microphthalmia-associated transcription factor (MITF). J Biol Chem 289:326-34
Young, Nicholas A; Friedman, Alexandra K; Kaffenberger, Benjamin et al. (2013) Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus. Mol Immunol 54:23-31
Sharma, Sudarshana M; Sif, Said; Ostrowski, Michael C et al. (2009) Defective co-activator recruitment in osteoclasts from microphthalmia-oak ridge mutant mice. J Cell Physiol 220:230-7
Sharma, Sudarshana M; Hu, Rong; Bronisz, Agnieszka et al. (2006) Genetics and genomics of osteoclast differentiation: integrating cell signaling pathways and gene networks. Crit Rev Eukaryot Gene Expr 16:253-77
So, Hongseob; Rho, Jaerang; Jeong, Daewon et al. (2003) Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem 278:24209-16
Mansky, Kim C; Sulzbacher, Sabine; Purdom, Georgia et al. (2002) The microphthalmia transcription factor and the related helix-loop-helix zipper factors TFE-3 and TFE-C collaborate to activate the tartrate-resistant acid phosphatase promoter. J Leukoc Biol 71:304-10

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