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).
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.
|Piemontese, Marilina; Onal, Melda; Xiong, Jinhu et al. (2016) Low bone mass and changes in the osteocyte network in mice lacking autophagy in the osteoblast lineage. Sci Rep 6:24262|
|Zhu, Meiling; Sun, Ben-Hua; Saar, Katarzyna et al. (2016) Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. J Bone Miner Res 31:864-73|
|Jilka, Robert L (2016) The Road to Reproducibility in Animal Research. J Bone Miner Res 31:1317-9|
|Fujiwara, Yuko; Piemontese, Marilina; Liu, Yu et al. (2016) RANKL (Receptor Activator of NFÎºB Ligand) Produced by Osteocytes Is Required for the Increase in B Cells and Bone Loss Caused by Estrogen Deficiency in Mice. J Biol Chem 291:24838-24850|
|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|
|Ye, Shiqiao; Fujiwara, Toshifumi; Zhou, Jian et al. (2016) LIS1 Regulates Osteoclastogenesis through Modulation of M-SCF and RANKL Signaling Pathways and CDC42. Int J Biol Sci 12:1488-1499|
|Fujiwara, Toshifumi; Ye, Shiqiao; Castro-Gomes, Thiago et al. (2016) PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight 1:e86330|
|Kim, Ha-Neui; Han, Li; Iyer, Srividhya et al. (2015) Sirtuin1 Suppresses Osteoclastogenesis by Deacetylating FoxOs. Mol Endocrinol 29:1498-509|
|Piemontese, Marilina; Onal, Melda; Xiong, Jinhu et al. (2015) Suppression of autophagy in osteocytes does not modify the adverse effects of glucocorticoids on cortical bone. Bone 75:18-26|
|Ucer, Serra; Iyer, Srividhya; Bartell, Shoshana M et al. (2015) The Effects of Androgens on Murine Cortical Bone Do Not Require AR or ERÎ± Signaling in Osteoblasts and Osteoclasts. J Bone Miner Res 30:1138-49|
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