Estrogen deficiency and bone loss: an inflammatory tale
M. Neale Weitzmann, Roberto Pacifici
M. Neale Weitzmann, Roberto Pacifici
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1186-1194. https://doi.org/10.1172/JCI28550.
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Category: Review Series

Estrogen deficiency and bone loss: an inflammatory tale

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.

Authors

M. Neale Weitzmann, Roberto Pacifici

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Figure 3

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

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Schematic representation of the main mechanisms and feedback interaction...
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.