Estrogen Receptor Signaling Pathways in Bone

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Project Summary Project 3 investigates the central theme of this program project grant (PPG), sympathetic nervous system (SNS) control of bone metabolism, by using a novel mouse model in Aim 1 to define the contribution of increased �-adrenergic receptor (�-AR) signaling to bone loss following estrogen (E) deficiency. Using microneurography, we found (see Project 1) that postmenopausal women have markedly increased sympathetic outflow as compared to premenopausal women. Moreover, in Project 3, we demonstrate that E treatment in vitro or E replacement in postmenopausal women markedly reduces �2-AR expression in osteoblastic cells, suggesting that E may modulate �-AR signaling in bone. Combined with previous studies indicating that, in mice, �2-ARs are the principal mediators of SNS effects on bone, these findings lead to our hypothesis in Aim 1 that E deficiency results in enhanced SNS signaling in bone and that �2-AR deletion in osteoblast lineage cells in adult mice at the time of ovariectomy (ovx) will prevent, or at least attenuate, ovx- induced bone loss. In Aims 2 and 3, Project 3 will better define E effects on bone metabolism beyond the interactions with SNS signaling being studied in Aim 1. For this, we will build on discoveries made previously in this PPG and will use novel mouse models that we have developed and validated. Thus, while skeleton is one of the main targets of E action, there are major gaps in our fundamental knowledge regarding E action on bone. First, all murine models of estrogen receptor (ER) action in mice have utilized deletions from conception onward, making it impossible to distinguish the effects of E on skeletal development from those on regulation of the adult skeleton or on age-related bone loss. We have developed and extensively validated a Cre- inducible system for deletion of ERs in the adult mouse. Our preliminary data using this system demonstrates that loss of ER� in adult mice has no effect on bone mass, whereas the uterus appears similar to an ovx d mouse. This suggests that in the complete absence of ER�, ER� may be compensating for the loss of ER� in bone. We will test this hypothesis in Aim 2, where we will determine if, in the absence of ER�, ER� compensates for loss of ER� in bone in adult mice. A second, major unresolved question is which cell type is most crucial for triggering bone loss when E is withdrawn in the adult mouse (or human)? This is a very different question from that addressed by current mouse knock out (KO) models which utilize osteoblast-, osteoclast-, or osteocyte-specific ER� deletion from conception onwards. Thus, while ER� deletion during skeletal development in each of these cell types affects bone mass and structure, none of these models address the issue of which cell type is most important for triggering bone loss following E deficiency in the adult animal. In Aim 3 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 necessary to trigger bone loss in the adult mouse and to mimic the effects of ovx.