Reactive oxygen species (ROS) are culprits of the adverse effects of both aging and estrogen deficiency on the skeleton, but it remains unclear whether and how aging and estrogen deficiency influence each other's negative impact on bone. ROS production is amplified in osteoblastic cells by the redox signaler p66[shc] To defend against increased ROS, FoxO transcription programs are acfivated. With increased ROS the generation of committed osteoblast precursors is restrained by diversion of B-catenin from Wnt/Tcf- to Fox mediated transcription. FoxOs also suppress osteoclast number and function. Loss of estrogen action in osteoclasts or osteoblasts increases ROS production and causes bone loss. It is hypothesized that the loss of cancellous bone results from increased osteoclastogenesis and decreased osteoclast apoptosis secondary to potentiation of RANKL-simulated NADPH/ROS signaling. The loss of cortical bone is caused by ROS-induced FoxO activation and attenuation of Wnt signaling and osteoblastogenesis. The contribution of ROS amplification by p66[shc] or ROS attenuation by FoxOs in osteoblasts and osteoclasts to skeletal homeostasis and its deregulation by aging will be investigated using mice in which ROS are decreased by deleting p66[shc] globally or overexpressing Fox03 in mature osteoblasts (expressing OCN), the entire osteoclast lineage (LysM), or mature osteoclasts (Cathepsin K). The role of ROS in the effects of estrogens on osteoblastic and osteoclastic cells and the contribution of the loss of estrogen action in these two cell types to skeletal involution will be studied, using the same mice as above as well as mice in which the ERo is deleted in Osterix (Osx) expressing osteoblast progenitors or the entire osteoclast lineage. In addition, the role of ROS and FoxO activation in the actions of estrogens will be investigated in vitro using sorted Osx cells from mice with and without ERa in this cell population;and effects of estrogens on RANKL-stimulated NADPH/ROS signaling in osteoclasts will be explored using bone marrow cultures of cells isolated from mice lacking p66[shc] or overexpressing Fox03 in osteoclasts. Lastly, the interplay among ERa, p66[shc] ROS, and FoxOs in the effects of estrogen deficiency on cortical bone will be investigated using mice in which ERa is deleted in Prxl cells;the ERa deletion in Prxl cells is combined with the global p66 deletion;FoxOI,3,4 are deleted in Osx cells;or the FoxOI,3,4 deletion is combined with the ERa deletion in Osx cells.
Osteoporosis is the commonest metabolic disorder of old age and age is the most critical predictor of fractures - the clinical manifestation of the slowly progressing and cumulative pathology causing this condition. For over sixty years, the disease has been attributed primarily to the decline of the function of ovaries at menopause, but our understanding of the effects of aging itself on the skeleton has remained very poor. The work proposed in this application will investigate the influence of oxidative stress on bone cells and how loss of estrogens and aging synergize in the development of this disease;and it may prove useful for developing novel drugs targeting pathways and mechanisms of aging that could prevent (or even reverse) osteoporosis and other degenerative disorders simultaneously.
|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|
|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|
|Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa et al. (2017) Estrogens and Androgens in Skeletal Physiology and Pathophysiology. Physiol Rev 97:135-187|
|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|
|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:|
|Fujiwara, Toshifumi; Ye, Shiqiao; Castro-Gomes, Thiago et al. (2016) PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight 1:e86330|
|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, 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|
|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|
|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|
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