Gonadectomy increases the generation of reactive oxygen species (ROS) in the murine skeleton and the adverse effects of the loss of ovarian or testicular function on bone can be prevented by anti-oxidants. Conversely, estrogens or non-aromatizable androgens decrease oxidative stress. The effects of estrogens result from DNA-binding independent actions of the ER1. In full agreement with such a mechanism, an estradiol dendrimer conjugate (EDC) that is not capable of stimulating the nuclear- initiated actions of ER1 reproduces the effects of estradiol on osteoclasts and osteoblasts;and is as potent as estradiol in preventing oxidative stress and ovariectomy-induced bone loss, without affecting uterine weight. ER1 deletion in cells of the osteoclast lineage (expressing Lys-M) causes loss of cancellous, but not cortical, bone in female mice;while ER1 deletion from mesenchymal progenitors (Prx1 expressing cells) decreases cortical thickness in both females and males. Consistent with the above, ROS attenuate osteoblastogenesis and shorten the lifespan of osteoblasts and osteocytes. On the other hand ROS are required for osteoclast generation, function, and survival. Moreover, loss or gain of function of FoxOs - transcription factors that are an important defense mechanism against oxidative stress (OS) -dramatically alters skeletal homeostasis. Based on these findings it is hypothesized that similar to ER1-mediated effects of estrogens, AR-mediated effects of androgens decrease ROS generation in both osteoblasts and osteoclasts via cell autonomous mechanisms. Conversely, androgen deficiency increases ROS production in either cell type, and in the adult male skeleton this leads to loss of both cancellous and cortical bone. The protective effect of androgens on cancellous bone is mediated primarily via the osteoclast AR and results from decreased osteoclastogenesis and shortened osteoclast lifespan secondary to increased apoptosis. The protective effect of androgens on cortical bone is mediated via both the AR and the ER1 and is caused by attenuation of ROS-induced FoxO activation and the resulting potentiation of Wnt signaling and osteoblastogenesis. The EDC will be protective of cortical bone in gonadectomised males, as it is in females, without affecting male reproductive organs such as seminal vesicles. To advance these interrelated hypotheses, the contribution of cell autonomous effects of androgens on osteoblasts to skeletal homeostasis will be investigated by determining the effects of AR deletion from Prx1, Osx, or DMP1 expressing cells in the skeleton of male mice;and the effects of AR-mediated androgen signaling on ROS and FoxO-activated pathways in vivo and in osteoblastic cells isolated from these mice. Further, the contribution of cell autonomous effects of androgens on osteoclasts to skeletal homeostasis will be studied by determining the effects of AR deletion from LysM and Cathepsin K expressing cells in the skeleton of male mice;and the effects of AR-mediated androgen signaling on ROS-activated pathways in vivo and in osteoclastic cells isolated from these mice. Lastly, the contribution of the ER1 deletion from osteoblastic cells to skeletal homeostasis in the male and the bone sparing efficacy of the EDC in androgen deficient wild type adult male mice will be determined.

Public Health Relevance

A deficiency of estrogens in females or both androgens and estrogens in males contributes to the development of osteoporosis in either sex. However, the mechanism(s) responsible for the adverse effects of the deficiency of either class of sex steroid on the male or female skeleton are not well understood;nor is the molecular mechanism(s) by which estrogens contribute to the maintenance of the male skeleton. The work proposed in this application will investigate how loss of androgens influences oxidative stress on bone cells and how it contributes to the development of this disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Endocrinology B (ENDB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Central Arkansas Veterans Hlthcare Sys
North Little Rock
United States
Zip Code
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
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
Kim, Ha-Neui; Han, Li; Iyer, Srividhya et al. (2015) Sirtuin1 Suppresses Osteoclastogenesis by Deacetylating FoxOs. Mol Endocrinol 29:1498-509
Ucer, Serra; Iyer, Srividhya; Bartell, Shoshana M et al. (2015) The Effects of Androgens on Murine Cortical Bone Do Not Require AR or ER? Signaling in Osteoblasts and Osteoclasts. J Bone Miner Res 30:1138-49
Carson, James A; Manolagas, Stavros C (2015) Effects of sex steroids on bones and muscles: Similarities, parallels, and putative interactions in health and disease. Bone 80:67-78
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
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
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

Showing the most recent 10 out of 17 publications