Estrogen deficiency and bone loss: an inflammatory tale - PubMed (original) (raw)

Review

Estrogen deficiency and bone loss: an inflammatory tale

M Neale Weitzmann et al. J Clin Invest. 2006 May.

Abstract

Estrogen plays a fundamental role in skeletal growth and bone homeostasis in both men and women. Although remarkable progress has been made in our understanding of how estrogen deficiency causes bone loss, the mechanisms involved have proven to be complex and multifaceted. Although estrogen is established to have direct effects on bone cells, recent animal studies have identified additional unexpected regulatory effects of estrogen centered at the level of the adaptive immune response. Furthermore, a potential role for reactive oxygen species has now been identified in both humans and animals. One major challenge is the integration of a multitude of redundant pathways and cytokines, each apparently capable of playing a relevant role, into a comprehensive model of postmenopausal osteoporosis. This Review presents our current understanding of the process of estrogen deficiency-mediated bone destruction and explores some recent findings and hypotheses to explain estrogen action in bone. Due to the inherent difficulties associated with human investigation, many of the lessons learned have been in animal models. Consequently, many of these principles await further validation in humans.

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Figures

Figure 1

Figure 1. Cells and cytokines responsible for physiological OC renewal.

OC precursors may differentiate from the population of monocytes/macrophages, among which they circulate by virtue of their expression of the receptor RANK. When RANKL binds to this receptor in the presence of the trophic factor M-CSF, which in turn binds to its receptor, colony-stimulating factor receptor 1 (c-Fms), OC precursors differentiate and fuse together to form mature, multinucleated bone-resorbing OCs. Under physiological conditions the dominant source of RANKL and M-CSF in the bone marrow microenvironment is from the bone-forming cells, the OBs, and their SC precursors.

Figure 2

Figure 2. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs.

In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7–dependent mechanism, resulting in a smaller pool of lymphoid progenitors. T cell precursors leave the bone marrow and migrate to the thymus, where T cell differentiation, selection, and expansion take place, in large measure under control of IL-7. Following release from the thymus (thymic output), these new T cells home to peripheral lymphoid organs, including the bone marrow itself. Estrogen prevents T cell activation in part by directly blunting antigen presentation and in part via repression of IL-7 and IFN-γ production. This effect is amplified by the upregulation of the IL-7 suppressor TGF-β. The net result of these actions is a decrease in the number of TNF-producing T cells. The blunted levels of TNF diminish RANKL-induced OC formation, ultimately preventing bone loss.

Figure 3

Figure 3. Schematic representation of the main mechanisms and feedback interactions by which estrogen deficiency leads to bone loss.

The bone loss induced by estrogen deficiency is due to a complex interplay of hormones and cytokines that converge to disrupt the process of bone remodeling. Estrogen deficiency leads to a global increase in IL-7 production in target organs such as bone, thymus, and spleen, in part through decreases in TGF-β and increased IGF-1 production. This leads to an initial wave of T cell activation. Activated T cells release IFN-γ, which increases antigen presentation by DCs and macrophages (Mϕ) by upregulating MHC class II expression through the transcription factor CIITA. Estrogen deficiency also amplifies T cell activation and osteoclastogenesis by downregulating antioxidant pathways, leading to an upswing in ROS. The resulting increase in ROS stimulates antigen presentation and the production of TNF by mature OCs. The combined effect of IFN-γ and ROS markedly enhances antigen presentation, amplifying T cell activation and promoting release of the osteoclastogenic factors RANKL and TNF. TNF further stimulates SC and OB RANKL and M-CSF production, in part via IL-1 upregulation, driving OC formation. TNF and IL-7 further exacerbate bone loss by blunting bone formation through direct repressive effects on OBs.

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