Wnt/2-catenin signaling is indispensable for osteoblastogenesis and bone formation. In studies leading to this application, a novel mechanism of Wnt/2-catenin antagonism, whereby activation of FoxO transcription factors diverts the limited pool of 2-catenin from Wnt induced TCF/Lef- transcription to FoxO-mediated transcription was elucidated. This antagonistic cascade in bone is initiated by reactive oxygen species (ROS) and represents both a mediator of, and a defense mechanism against, oxidative stress. FoxOs mediate oxidative stress responses by regulating the expression of genes involved in cell cycle, DNA repair, and lifespan. The involvement of the histone deacetylase Sirt1 in the inhibition of Wnt/2-catenin by ROS;and co- activation by 2-catenin of the expression of FoxO-target genes that promote osteoblast survival under stress conditions was also established. Moreover, evidence was obtained that the actions of glucocorticoids or TNF1 on bone are mediated, at least in part, by ROS-induced FoxO activation. The above observations form the foundation of the hypothesis that activation of FoxO transcription factors by oxidative stress represents a previously unappreciated cell-autonomous mechanism of Wnt/2-catenin antagonism which contributes to the adverse effects of aging, glucocorticoid excess and inflammatory cytokines on bone, by diverting 2-catenin from TCF- to FoxO-mediated transcription. To test this hypothesis, the role of ROS-induced FoxO post- translational modifications on the binding of FoxOs to 2-catenin, in osteoblastic cells, and whether ROS lead to recruitment of 2-catenin to the promoter of FoxO-target genes will be investigated (Aim 1). In addition, in vitro studies will be done to establish the consequences of FoxO activation in osteoblast lifespan and differentiation (Aim 2). Finally, mice overexpressing FoxO3a in osteoblast precursors and their progeny (osteoblasts, osteocytes);and mice in which the three main FoxO isoforms FoxO1, 3a, and 4 are conditionally deleted will be used to examine the role of FoxOs in skeletal homeostasis (Aim 3). This work should advance knowledge of how aging, glucocorticoid excess or inflammatory cytokines decrease bone mass. Furthermore, it should provide a better understanding of how to optimize the treatment of this condition.

Public Health Relevance

The proposed studies seek to identify the means by which aging, glucocorticoid excess or inflammatory cytokines cause bone loss. This will be accomplished by studying changes in the function of proteins that control bone-forming cells. Increased understanding of the mechanisms that control bone formation will provide important information for the development of therapies to maintain or increase bone mass and strength, thereby reducing the risk of osteoporotic fractures

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056679-03
Application #
8225401
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2010-04-15
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$313,200
Indirect Cost
$97,200
Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Manolagas, Stavros C (2014) Wnt signaling and osteoporosis. Maturitas 78:233-7
Manolagas, Stavros C; Kronenberg, Henry M (2014) Reproducibility of results in preclinical studies: a perspective from the bone field. J Bone Miner Res 29:2131-40
Bartell, Shoshana M; Kim, Ha-Neui; Ambrogini, Elena et al. (2014) FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun 5:3773
Iyer, Srividhya; Han, Li; Bartell, Shoshana M et al. (2014) Sirtuin1 (Sirt1) promotes cortical bone formation by preventing ?-catenin sequestration by FoxO transcription factors in osteoblast progenitors. J Biol Chem 289:24069-78
Almeida, Maria; O'Brien, Charles A (2013) Basic biology of skeletal aging: role of stress response pathways. J Gerontol A Biol Sci Med Sci 68:1197-208
Iyer, Srividhya; Ambrogini, Elena; Bartell, Shoshana M et al. (2013) FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest 123:3409-19
Manolagas, Stavros C (2013) Steroids and osteoporosis: the quest for mechanisms. J Clin Invest 123:1919-21
Almeida, Maria; Iyer, Srividhya; Martin-Millan, Marta et al. (2013) Estrogen receptor-* signaling in osteoblast progenitors stimulates cortical bone accrual. J Clin Invest 123:394-404
Bartell, Shoshana M; Han, Li; Kim, Ha-neui et al. (2013) Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. Mol Endocrinol 27:649-56
Almeida, Maria (2011) Unraveling the role of FoxOs in bone--insights from mouse models. Bone 49:319-27

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