NFATc1, NF?B, cFOS, PU.1/SPI1 and MITF are transcription factors (TFs) essential for osteoclast differentiation from myeloid precursors. However, large gaps still remain in our understanding of the interplay between these TFs and how this interplay contributes to osteoclast differentiation and function. Importantly, critical questions about how the dynamics of TF regulation contributes to clinical outcome of human bone related diseases are unresolved. During the last cycle of this grant we used newly available functional genomic approaches and new bioinformatics approaches to develop a hierarchical network model that explains the interactions between these factors and their relative roles in osteoclast differentiation. Based on this model our overriding hypothesis is that PU.1 and MITF are at the apex of an osteoclast transcription factor network in osteoclasts and their myeloid precursors that initiates and maintains the differentiated state in response to signals received from the local microenvironment. In the current proposal, we aim to test this model using both in vivo and in vitro experiments and importantly to extend these studies into normal human osteoclasts and circulating osteoclast precursors from rheumatoid arthritis patients. Further we will test the importance of this network and associated factors in a preclinical mouse model for rheumatoid arthritis, using approaches that genetically target Pu.1 or use small molecule inhibitors to target PU.1/MITF-dependent epigenetic changes in pre-osteoclasts. By combining our efforts and expertise, our multidisciplinary team will focus on the task of understanding the mechanisms that govern osteoclast differentiation and function, and the relevance of these factors in human osteoclasts.

Public Health Relevance

Osteoclasts are cells required for normal bone growth and homeostasis, but they often inappropriately destroy bone in human diseases, including in osteoporosis, rheumatoid arthritis and tumor metastasis to bone. Our work has taken advantage of information from genome sequencing projects to study how osteoclasts are formed and regulated in mice. This work has provided paradigm-shifting insights into how osteoclasts are regulating. In the proposed work we will attempt to better understand the mechanisms that regulate osteoclasts implied by our genomic studies and attempt to translate these finding to normal human osteoclasts and rheumatoid arthritis patient osteoclasts.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Alekel, D Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Medicine
United States
Zip Code
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
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
Mansky, Kim C; Marfatia, Kavita; Purdom, Georgia H et al. (2002) The microphthalmia transcription factor (MITF) contains two N-terminal domains required for transactivation of osteoclast target promoters and rescue of mi mutant osteoclasts. J Leukoc Biol 71:295-303
Mansky, Kim C; Sankar, Uma; Han, Jiahuai et al. (2002) Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. J Biol Chem 277:11077-83
Luchin, A; Suchting, S; Merson, T et al. (2001) Genetic and physical interactions between Microphthalmia transcription factor and PU.1 are necessary for osteoclast gene expression and differentiation. J Biol Chem 276:36703-10
Luchin, A; Purdom, G; Murphy, K et al. (2000) The microphthalmia transcription factor regulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts. J Bone Miner Res 15:451-60