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.

The Effect of Estrogen on Bone Marrow-Derived Rat Mesenchymal Stem Cell Maintenance: Inhibiting Apoptosis Through the Expression of Bcl-xL and Bcl-2

“…1b and c). Bone marrow is one of the target tissues of estrogen and osteoblasts, osteocytes, osteoclasts, T cells and B cells in human and mouse bone marrow express both ERα and ERβ [29]. Our results showed that rat bone marrow-derived MSCs also express ERα and ERβ (Fig.…”

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

“…Although the mechanisms of these diseases are distinct, excessive activity of osteoclasts (OCs) is a common feature and hallmark of osteoporosis. (1) OCs, the major bone-resorbing cells, are derived from mononuclear precursors of the monocyte/macrophage lineage, such as bone marrow macrophages (BMMs). In response to the cytokines, receptor activator of NF-kB ligand (RANKL), and macrophage colony-stimulating factor (M-CSF), monocyte precursors differentiate into pre-OCs that ultimately fuse to form polykaryons with the capacity to resorb mineralized substrates such as bone.…”

Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand

“…The acute effects of menopause are modeled by ovariectomy (ovx) which, like natural menopause, stimulates bone resorption by increasing osteoclast (OC) formation (3,4) and lifespan (5,6). The net bone loss caused by ovx is limited by an increase in bone formation resulting from stimulated osteoblast (OB) formation (7).…”

“…OC formation occurs when bone marrow macrophages (BMMs) are stimulated by the osteoclastogenic factors receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) (10,11); however, in conditions of E deficiency, the secretion of the RANKL decoy receptor osteoprotegerin (OPG) decreased (12), whereas RANKL and other cytokines, including TNF-α, IL-1, IL-6, IL-7, and M-CSF, are produced in greater amounts (3,13,14). The compensatory increase in bone formation that follows ovx is mitigated by some of these factors, primarily TNF and IL-7, which blunt osteoblastogenesis (15,16).…”