The overall goal of this study is to understand the mechanism underlying transcription factors specifying osteoclast lineage commitment and differentiation. This proposal is highly significant since elucidating osteoclast lineage commitment and differentiation has potential to define new therapeutic targets for bone disorders that involve osteoclast generation and activation. Despite the recent insights gained from the effects of targeted deletion of the c-fos, PU.1, NF-?B, and NFATc1 transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lino define new therapeutic targets for bone disorders that involve osteoclast generation and activation. Despite the recent insights gained from the effects of targeted deletion of the c-fos, PU.1, NF-?monstrated that AML1 is highly induced by RANKL and M-CSF together. AML1 knockdown in mouse bone marrow culture induced by RANKL and M-CSF blocked osteoclast differentiation, but did not inhibit macrophage differentiation. However, AML1-/- liver cells failed to develop both monocytes/macrophages and osteoclasts. Our results showed that that AML1 may control osteoclast cell lineage commitment and regulate osteoclast gene expression and differentiation through upregulating PU.1 and NFATc1. Based on our Preliminary study, we hypothesize that AML1 is a key regulator that specifies osteoclast cell lineage commitment and differentiation at the transcriptional regulation level. We will test this hypothesis through two specific aims. We will define the functional role of AML1 in osteoclast cell lineage commitment and differentiation using RNAi knockdown and overexpression in Aim 1. We will investigate the role of AML1 in osteoclast differentiation in adult mice through bone tissue-specific targeted disruption of AML using a conditional knockout approach by Cre/loxP technology and characterize the phenotypes and pathomechanism of the AML1 conditional knockout mice. Ultimately, this knowledge will help to establish the roles of AML1 in osteoclast cell lineage commitment and differentiation. Thus, it will improve our understanding of osteolytic diseases and help to design novel approaches for the treatment of diseases such as osteoporosis, arthritis, periodontal disease, and bone metastases using drug or somatic gene therapy.

Public Health Relevance

The overall goal of this study is to understand the mechanism underlying transcription factors specifying osteoclast lineage commitment and differentiation. This proposal is highly significant since elucidating osteoclast lineage commitment and differentiation has potential for defining new therapeutic targets for bone disorders that involve osteoclast generation and activation. Thus, it will improve our understanding of osteolytic diseases and help to design novel approaches for the treatment of diseases such as osteoporosis, arthritis, periodontal disease, and bone metastases] using drug or somatic gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055307-02
Application #
7924070
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2009-09-01
Project End
2010-09-30
Budget Start
2010-09-01
Budget End
2010-09-30
Support Year
2
Fiscal Year
2010
Total Cost
$76,847
Indirect Cost
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Tian, Fei; Wu, Mengrui; Deng, Lianfu et al. (2014) Core binding factor beta (Cbf?) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and J Bone Miner Res 29:1564-1574
Yang, Sen; Hao, Liang; McConnell, Matthew et al. (2013) Inhibition of Rgs10 Expression Prevents Immune Cell Infiltration in Bacteria-induced Inflammatory Lesions and Osteoclast-mediated Bone Destruction. Bone Res 1:267-281
Ma, Junqing; Chen, Wei; Zhang, Lijie et al. (2013) RNA interference-mediated silencing of Atp6i prevents both periapical bone erosion and inflammation in the mouse model of endodontic disease. Infect Immun 81:1021-30
Chen, Wei; Zhu, Guochun; Hao, Liang et al. (2013) C/EBP? regulates osteoclast lineage commitment. Proc Natl Acad Sci U S A 110:7294-9

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