MOLECULAR MECHANISMS OF THE SKELETAL EFFECTS OF ESTROGEN IN OLD AGE

Univ Of Arkansas For Med Scis, Little Rock AR

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Abstract

Estrogen loss increases osteoclastogenesis, decreases osteoclast and increases osteoblast apoptosis, and[unreadable] causes loss of bone by decreasing anti-oxidant defense in these cell types. In addition, an age-dependent[unreadable] decrease in bone strength and mass in ovary-intact C57BL/6 mice is temporally associated with an agedependent[unreadable] increase in the prevalence of osteoblast apoptosis, decreased glutathione reductase (GSR)[unreadable] activity and corresponding increases in the production of reactive oxygen species (ROS) in the bone marrow[unreadable] and the phosphorylation of p66shc in vertebrae. Based on this evidence, it is hypothesized that increased[unreadable] ROS levels with advancing age is a fundamental mechanism of the age-dependent decline of bone strength[unreadable] and mass, and loss of estrogens exaggerates the adverse effects of aging on bone by decreasing defense[unreadable] against ROS, thereby, contributing perpetually to the loss of bone mass and strength that persists for[unreadable] decades after menopause, and is associated with old age. Estrogens enhance defense against ROS by[unreadable] modulating the activity of anti-oxidant enzymes, attenuating ROS-mediated induction of cytokines, and[unreadable] modulating signaling cascades that have been implicated in the defense against oxidative stress, apoptosis,[unreadable] and aging. All these effects are mediated by extranuclear (nongenotropic) actions of the ER on cytoplasmic[unreadable] kinases and result in changes in the birth and lifespan of osteoblasts, osteoclasts, and osteocytes. To test[unreadable] these interrelated hypotheses, in vitro studies are proposed to investigate whether the effects of estrogens[unreadable] on osteoblast and osteoclast apoptosis, as well as on osteoclastogenesis, are, at least in part, a direct[unreadable] consequence of the ability of these hormones to: a) antagonize the actions of ROS by increasing the levels[unreadable] of glutathione; and/or b) counteract ROS-activated signals on cytoplasmic kinases, and/or downstream[unreadable] transcription factors and the resulting upregulation of cytokines. Further, the role of oxidative stress in the[unreadable] molecular and cellular mechanism responsible for the loss of bone strength and mass associated with aging[unreadable] and the extent to which estrogen deficiency and the resulting attenuation of defense against oxidative stress[unreadable] in osteoblasts or osteoclasts contributes to these changes will be studied in mice over-expressing GSR in[unreadable] osteoblasts or osteoclasts. Finally, mice in which ERa will be deleted from osteoblasts or osteoclasts by[unreadable] means of CreXLoxP recombination; mice heterozygotes for an ERa knock-in mutant which cannot bind to[unreadable] ERE; and mice over-expressing an ERa mutant, which is incapable of membrane localization and prevents[unreadable] kinase-mediated signaling of the endogenous receptor, will be used to examine whether the antioxidant[unreadable] actions of estrogens on osteoblasts and osteoclasts in vivo are ER-dependent and nongenotropic. This work[unreadable] should help us understand how women become increasingly more susceptible to fractures as they grow old.[unreadable] Moreover, it mav lead to the discovery of more effective treatments or even a cure for osteoporosis.