Wnt/?-catenin signaling is indispensable for bone formation and the maintenance of bone mass in animals and humans. Compromised Wnt signaling plays a pathogenetic role in the development of the acquired forms of osteoporosis - not just the hereditary forms. Likewise, a decline in NAD+, Sirt1 activity and mitochondria ATP production have been implicated in several age related diseases. FoxO transcription factors attenuate Wnt signaling in lineage-committed osteoblast progenitors and, thereby, restrain their proliferation and the supply of matrix synthesizing osteoblasts. This results from the binding of FoxOs to ?-catenin and the sequestration of ?-catenin away from TCF-mediated transcription. Deacetylation of FoxOs by Sirt1 attenuates the binding of FoxOs to ?-catenin. Thus, Sirt1 in osteoprogenitor cells increases Wnt signaling and bone formation. In addition, Wnt signaling increases ATP production via a Sirt1-dependent mechanism while FoxOs decrease ATP production. FoxOs also act in osteoclast progenitors to restrain osteoclastogenesis. This effect results from direct binding of FoxOs to DNA and upregulation of catalase gene transcription. Sirt1 stimulates FoxO-mediated transcription in osteoclast progenitors, thereby inhibiting osteoclastogenesis. The above observations form the foundation of the hypothesis that Sirt1 increases osteoblastogenesis and decreases osteoclastogenesis by deacetylating FoxOs in the respective progenitors. The age-dependent decrease in Sirt1 activity contributes to the pathogenesis of involutional osteoporosis, by tilting the balance between bone formation and resorption, in favor of the latter. Activation of Sirt1 can ameliorate these effects and may, thus, represent a rational therapeutic target for the management of osteoporosis. The beneficial effects of Sirt1 on osteoblastogenesis are amplified by increased ATP production. To test this hypothesis we will investigate the role of FoxO deacetylation in the effects of Sirt1 on bone formation and resorption using mice in which the endogenous FoxO1, 3 and 4 in osteoblast or osteoclast progenitors are replaced with FoxO1 acetylation mutant proteins; or Sirt1 is overexpressed in the presence or absence of FoxOs (Aim 1). In addition, we will examine whether stimulation of Sirt1 antagonizes the adverse effects of aging on bone using mice in which Sirt1 is overexpressed in osteoblast or osteoclast progenitors (Aim 2). Finally, we will perform in vitro studies to determine the contribution of mitochondria ATP production to osteoblastogenesis and the mechanisms via which FoxOs, Sirt1 and Wnt signaling modulate mitochondria function. This work should advance knowledge of how aging decreases bone mass. Furthermore, it should suggest novel therapies to optimize the treatment of osteoporosis.

Public Health Relevance

Osteoporosis is one of the most common features of human aging, but the mechanisms responsible for this condition remain unclear. As it is unclear whether these mechanisms are specific for bone or are shared by other tissues and organs. The work proposed in this application seek to identify the means by which aging causes bone loss by studying changes in the function of proteins that control both the bone-resorbing cells and the bone-forming cells. Increase understanding of the mechanisms that control bone cells may prove useful for the development of therapies that can treat osteoporosis and other degenerative disorders of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056679-07
Application #
9212784
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Alekel, D Lee
Project Start
2008-12-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
7
Fiscal Year
2017
Total Cost
$295,020
Indirect Cost
$97,020
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
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