Osteoporosis is a bone disease affecting nearly 1 in 3 women worldwide and over 55% of all Americans resulting in health care costs exceeding 19 billion dollars annually in the United States alone. Since the discovery of the TGF? inducible early gene-1 (TIEG) by our laboratory, we have demonstrated that loss of TIEG expression in mice results in multiple defects in osteoblasts and osteoclasts and confers a gender specific osteopenic phenotype affecting only female animals. Recently, TIEG has been identified as one of only a few genes whose altered expression levels or allelelic variations associate with decreased bone mass and osteoporosis in humans. During the past funding period, we have shown that TIEG expression is essential for estrogen signaling in bone and have identified a novel role for TIEG in mediating canonical Wnt signaling in the skeleton. These observations are of significant interest since estrogen remains one of the most important regulators of bone homeostasis in both men and women and since Wnt signaling is essential for normal bone development and maintenance. For these reasons, it is crucial to understand the regulation of these pathways in the skeleton. In this proposal, we present evidence that TIEG enhances the Wnt signaling pathway via dual mechanisms whereby it directly suppresses the expression of sclerostin and serves as a transcriptional co- activator for ?-catenin. Furthermore, our data suggest that TIEG serves as a direct link between the estrogen and canonical Wnt pathways in bone. Based on these observations, our central hypothesis is that TIEG is a crucial component of canonical Wnt signaling and serves a central role in regulating cross-talk between the estrogen and Wnt pathways in the skeleton. In order to test this hypothesis, the following Specific Aims are proposed: 1): Characterize the regulation of sclerostin gene expression by TIEG and determine its contribution to the observed osteopenic phenotype of TIEG knockout mice;2): Characterize the ability of TIEG to enhance canonical Wnt signaling through co-activation of ?-catenin;and 3) Determine if the gender specific (female only) osteopenic phenotype of TIEG KO mice results from defective cross-talk between the estrogen and canonical Wnt signaling pathways in bone. To address these Specific Aims, we will employ in vitro approaches to identify the molecular mechanisms by which TIEG suppresses sclerostin expression in osteocytes and enhances ?-catenin function in osteoblasts. Additionally, we will utilize multiple in vivo models and approaches to dissect the role of TIEG in regulating canonical Wnt pathway activity and cross-talk between estrogen and Wnt signaling in the skeleton. Considering the fundamental roles of estrogen and Wnt signaling in bone, as well as the present day targeting of these pathways for the treatment of osteoporosis, it is essential to understand the role of TIEG in regulating these two pathways. Completion of the proposed studies is therefore expected to provide significant knowledge with regard to developing novel strategies to treat this debilitating disease.

Public Health Relevance

Osteoporosis is a skeletal disease characterized by decreased bone mineral density and altered bone microarchitecture which ultimately results in bone fractures. Osteoporosis affects approximately 55% of all Americans resulting in health care costs of nearly 19 billion dollars annually, a figure that is expected to surpass 25 billion dollars by the year 2025. This project involves determining the role of TIEG, one of only a handful of genes identified to be clinically associated with the development of osteoporosis in humans, in regulating the canonical Wnt and estrogen signaling pathways in bone. Outcomes of the proposed studies are expected to further our understanding of osteoporosis and aid in the development of novel therapies to treat this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE014036-10
Application #
8369584
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wan, Jason
Project Start
2001-09-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$408,350
Indirect Cost
$144,550
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Hawse, John R; Pitel, Kevin S; Cicek, Muzaffer et al. (2014) TGF* inducible early gene-1 plays an important role in mediating estrogen signaling in the skeleton. J Bone Miner Res 29:1206-16
Zhang, Wei; Wang, Xuelian; Xia, Xiaoping et al. (2013) Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages. Eur J Immunol 43:258-69
Yin, Ke-Jie; Fan, Yanbo; Hamblin, Milton et al. (2013) KLF11 mediates PPARýý cerebrovascular protection in ischaemic stroke. Brain 136:1274-87
Cicek, Muzaffer; Vrabel, Anne; Sturchio, Catherine et al. (2011) TGF-? inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways. PLoS One 6:e17522
Haddad, Oualid; Gumez, Laurie; Hawse, John R et al. (2011) TIEG1-null tenocytes display age-dependent differences in their gene expression, adhesion, spreading and proliferation properties. Exp Cell Res 317:1726-35
Subramaniam, M; Hawse, J R; Bruinsma, E S et al. (2010) TGFbeta inducible early gene-1 directly binds to, and represses, the OPG promoter in osteoblasts. Biochem Biophys Res Commun 392:72-6
Kim, Joanna; Shin, Sook; Subramaniam, Malayannan et al. (2010) Histone demethylase JARID1B/KDM5B is a corepressor of TIEG1/KLF10. Biochem Biophys Res Commun 401:412-6
Subramaniam, Malayannan; Hawse, John R; Rajamannan, Nalini M et al. (2010) Functional role of KLF10 in multiple disease processes. Biofactors 36:8-18
Hawse, J R; Subramaniam, M; Ingle, J N et al. (2008) Estrogen-TGFbeta cross-talk in bone and other cell types: role of TIEG, Runx2, and other transcription factors. J Cell Biochem 103:383-92
Subramaniam, Malayannan; Hawse, John R; Johnsen, Steven A et al. (2007) Role of TIEG1 in biological processes and disease states. J Cell Biochem 102:539-48

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