Despite the importance of estrogen (E) in regulating bone metabolism and age-related bone loss, there remain fundamental, unanswered questions regarding E action on bone. A more complete understanding of E regulation of bone turnover is important because even though E treatment of postmenopausal women is declining due to well publicized non-skeletal risks, understanding the mechanisms by which E regulates bone metabolism is likely to identify novel therapeutic targets. Existing mouse models with cell-specific deletion of estrogen receptor (ER)? have provided significant mechanistic insights, but an important limitation of all current models is that they have involved ER deletion from conception onwards, making it impossible to distinguish the effects of E on skeletal development from those on the adult skeleton. To address this issue, we have developed an experimental model in which we can selectively delete ER? in the adult mouse. In preliminary studies in which ER? was globally deleted in adult mice while holding circulating E levels constant, we surprisingly found no bone loss or increase in bone resorption despite marked decreases in uterine weight to levels observed following ovariectomy. These data establish a unique approach to define the role of ER? in regulating bone turnover in the adult skeleton, and also point to a potential compensatory mechanism in bone that has been largely ignored. We hypothesize that this mechanism involves ER, and in Aim 1, we will globally delete both ER? and ER following skeletal maturity and determine whether the absence of bone loss we observed following ER? deletion alone in the adult mouse was due to ER compensation. A second important, unresolved question is that when E is withdrawn in the adult mouse (or human), which cell type is crucial for triggering bone loss? In Aim 2 we will test the hypothesis that this crucial cell is the osteocyte, and that deletion of both ER? and ER in the osteocyte will be required to trigger bone loss in the adult mouse. The existing evidence in support of this hypothesis is that 1) the osteocyte is increasingly recognized as the master regulator of bone remodeling; 2) prevention of osteocyte apoptosis also prevents the increase in bone resorption following ovariectomy; and 3) both ER? and ER activate extracellular signal- related kinases that mediate the anti-apoptotic effects of E on osteocytes. A competing hypothesis to the osteocyte being the crucial cell triggering bone remodeling following E deficiency is that the key cell is, in fact, the osteoclast. Thus, mice with ER? deletion in osteoclasts from conception onwards have increased bone turnover and reduced bone mass. In order to definitively resolve this issue, in Aim 3 we will delete ER? and/or ER in osteoclasts in the adult mouse and compare this to osteocyte-specific deletion of these receptors in Aim 2. Moreover, embedded within Aims 2 and 3 will be analyses of highly enriched populations of osteocytes, osteoclast progenitors, and osteoblasts that are performed without in vitro culture, thereby providing important mechanistic insights into E action on bone.
Despite the importance of estrogen in regulating bone metabolism and age-related bone loss, there remain fundamental, unanswered questions regarding estrogen action on bone. This proposal seeks to identify the key cells and pathways in bone that mediate the effects of estrogen on the skeleton. This may, in turn, identify novel therapeutic targets to prevent or reverse bone loss with aging.
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