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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arkansas for Medical Sciences
Little Rock
United States
Zip Code
Farr, Joshua N; Almeida, Maria (2018) The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging. J Bone Miner Res 33:1568-1584
Weinstein, Robert S; Hogan, Erin A; Borrelli, Michael J et al. (2017) The Pathophysiological Sequence of Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Male Mice. Endocrinology 158:3817-3831
Kim, Ha-Neui; Chang, Jianhui; Shao, Lijian et al. (2017) DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell 16:693-703
Ucer, Serra; Iyer, Srividhya; Kim, Ha-Neui et al. (2017) The Effects of Aging and Sex Steroid Deficiency on the Murine Skeleton Are Independent and Mechanistically Distinct. J Bone Miner Res 32:560-574
Iyer, Srividhya; Han, Li; Ambrogini, Elena et al. (2017) Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes. J Bone Miner Res 32:60-69
Almeida, Maria; Laurent, Michaƫl R; Dubois, Vanessa et al. (2017) Estrogens and Androgens in Skeletal Physiology and Pathophysiology. Physiol Rev 97:135-187
Piemontese, Marilina; Almeida, Maria; Robling, Alexander G et al. (2017) Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight 2:
Piemontese, Marilina; Xiong, Jinhu; Fujiwara, Yuko et al. (2016) Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. Am J Physiol Endocrinol Metab 311:E587-93
Fujiwara, Toshifumi; Ye, Shiqiao; Castro-Gomes, Thiago et al. (2016) PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight 1:e86330
Fujiwara, T; Zhou, J; Ye, S et al. (2016) RNA-binding protein Musashi2 induced by RANKL is critical for osteoclast survival. Cell Death Dis 7:e2300

Showing the most recent 10 out of 162 publications