The overall goal of this project is to identify mechanisms that decrease bone strength with age. We have shown that osteocyte viability decreases with age and that this is associated with increased oxidative stress, reduced bone vascular volume, decreased solute transport in the lacunar-canalicular system, and a decrease in bone strength this is disproportionate to the decrease in bone mass. We have also shown that blocking glucocorticoid action in osteoblast-lineage cells prevents many of these changes and that glucocorticoids increase oxidative stress. We also showed that resistance to oxidative stress, provided by the FoxO family of transcription factors, is essential for osteocyte survival. In addition, we have shown that autophagy-related genes are active in osteocytes and that expression of these genes decreases with age. Importantly, suppression of autophagy in osteocytes results in low bone mass in adult mice. Therefore, we will pursue the hypothesis that elevated levels of endogenous glucocorticoids contribute to the age associated decrease in bone strength by directly stimulating osteocyte apoptosis via increased oxidative stress and that this is opposed by the process of autophagy. which becomes less efficient with age. To advance this hypothesis, we will determine whether the effects of aging and exogenous glucocorticoids on bone strength and vasculature are due in part to effects of glucocorticoids on osteocytes only (as opposed to both osteoblasts and osteocytes) by gain and loss of glucocorticoid action in osteocytes (Aim 1). The role of reactive oxygen species (ROS) in the actions of glucocorticoids will be addressed by enhancing defense against ROS, via over-expression of FoxOS or by deleting the ROS amplifier p66^*"^ (Aim 2). In this aim we will also determine whether reduced defense against oxidative stress, by specifically deleting FoxOI. 3, and 4 in osteocytes. will mimic or accelerate the effects of aging. Lastly, we will determine whether autophagy in osteocytes changes with age and whether this process plays a role in maintaining osteocyte function and viability by measuring markers of autophagic flux in osteocytes of young and old mice and by conditional deletion of ATG7, which is essential for autophagy (Aim 3).

Public Health Relevance

Successful completion of these studies should establish whether oxidative stress contributes to the decline of osteocyte viability and function with age and how this decline leads to the earlier and greater loss of bone strength, compared to bone mass, that occurs with advanced age. Establishment of such a relationship may point the way to novel approaches to maintain osteocyte function and viability in aged individuals, thereby leading to increased skeletal strength.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG013918-17
Application #
8463083
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
17
Fiscal Year
2013
Total Cost
$278,170
Indirect Cost
$89,580
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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
Xiong, Jinhu; Piemontese, Marilina; Thostenson, Jeff D et al. (2014) Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency. Bone 66:146-54
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
Bellido, Teresita (2014) Osteocyte-driven bone remodeling. Calcif Tissue Int 94:25-34
Manolagas, Stavros C (2014) Wnt signaling and osteoporosis. Maturitas 78:233-7
Jilka, Robert L; O'Brien, Charles A; Roberson, Paula K et al. (2014) Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates cortical porosity with age. J Bone Miner Res 29:103-17
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
Plotkin, Lilian I; Bellido, Teresita (2013) Beyond gap junctions: Connexin43 and bone cell signaling. Bone 52:157-66
Onal, Melda; Piemontese, Marilina; Xiong, Jinhu et al. (2013) Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem 288:17432-40
Zhou, Jian; Ye, Shiqiao; Fujiwara, Toshifumi et al. (2013) Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation. J Biol Chem 288:30064-74

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