Dissertation/Thesis Abstract

The effects of sex steroids and reactive oxygen species on the maintenance of the skeleton
by Ucer, Semahat Serra, Ph.D., University of Arkansas for Medical Sciences, 2016, 136; 10146404
Abstract (Summary)

Old age and the decline in estrogen or androgens cause loss of bone mass and an increase in the risk of osteoporotic fractures. During growth androgens promote expansion and thickening of cortical bone. In addition, androgens decrease the number of osteoclasts and bone resorption in both the cancellous and cortical bone compartments. Androgen acting via the androgen receptor (AR) on osteoblasts and osteocytes are critical for attenuating the osteoclast number in cancellous bone in males. However, the cellular and molecular targets responsible for the effects of androgens on the cortical bone remain unknown. An increase in reactive oxygen species (ROS) in bone has been associated with both estrogen and androgen deficiency as well as aging. Nevertheless, the contribution of ROS generation in cells of the osteoblast and osteoclast lineage to the bone loss that occurs in these conditions is unknown.

I have investigated whether androgens act on bone via the AR or the estrogen receptor (ER) α, upon aromatization of testosterone to estradiol, and whether the effects of androgens are exerted on mesenchymal progenitors or osteoclasts. To this end, we generated mouse models lacking AR in the mesenchymal stem cells expressing Prx1 or in the myeloid cells expressing LysM; we also generated mice lacking ERα in the osteoblast progenitors expressing Osx1 or in the myeloid cells expressing LysM. I found that actions in all these cell types are dispensable for the protective effects of androgens on cortical bone in male mice. In agreement with others, we observed that androgens actions on the osteoblast lineage are responsible for their protective effects on the cancellous bone mass. These actions lead to a decrease in osteoclast number, most likely by suppressing soluble RANKL levels and B-lymphopoiesis.

We also generated mice, in which the antioxidant catalase has been targeted to the mitochondria of myeloid or mesenchymal progenitors, which causes attenuation of ROS in these cell types. Reduction of ROS in cells of the myeloid lineage prevented the increase in osteoclast number and loss of cortical bone caused by ovariectomy (OVX) or orchidectomy (ORX). In contrast, attenuation of ROS in cells of the myeloid lineage has no impact on the loss of bone caused by aging. Reduction of ROS in cells of the mesenchymal lineage attenuated the decline in the bone formation and loss of cortical bone caused by aging.

Our findings indicate that the actions of androgens on the expansion of cortical bone during growth are mediated by cells other than those of the osteoblast and osteoclast lineage. In cancellous bone, androgen signaling via AR expressed in the cells of the mesenchymal lineage attenuates osteoclastogenesis, likely by decreasing the number of B-lymphocyte, and RANKL. Additionally, we showed that an important mechanism of both the adverse effects of sex steroid deficiency and aging on cortical bone is an increase in ROS, but in different cell types. Increased ROS generation in cells of the mesenchymal lineage contribute to the decrease in bone formation and the age-dependent cortical bone loss. On the other hand, increased ROS generation in cells of the myeloid lineage contributes to the increase in bone resorption and cortical bone loss caused by sex steroid deficiency.

Indexing (document details)
Advisor: Almeida, Maria
Commitee: Kilic, Fusun, Manolagas, Stavros C., McGehee, Robert E., O'brien, Charles A.
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 78/02(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Endocrinology, Aging
Keywords: Aging, Bone, Osteoblast, Osteoclast, Reactive oxygen species, Sex steroids
Publication Number: 10146404
ISBN: 978-1-369-01763-2
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