Estrogen and the skeleton

Abstract

Estrogen is the major hormonal regulator of bone metabolism in women and men. Therefore, there is considerable interest in unraveling the pathways by which estrogen exerts its protective effects on bone. Although the major consequence of the loss of estrogen is an increase in bone resorption, estrogen deficiency is associated with a gap between bone resorption and formation, indicating that estrogen is also important for maintaining bone formation at the cellular level. Direct estrogen effects on osteocytes, osteoclasts, and osteoblasts lead to inhibition of bone remodeling, decreased bone resorption, and maintenance of bone formation, respectively. Estrogen also modulates osteoblast/osteocyte and T-cell regulation of osteoclasts. Unraveling these pleiotropic effects of estrogen may lead to new approaches to prevent and treat osteoporosis.

Figure 1. Schematic of the bone remodeling compartment

The bone remodeling compartment (BRC) comprises the cells constituting the basic multicellular unit (BMU) — specifically osteoclasts (OCs), osteoblasts (OBs), and osteocytes — as well as the canopy of bone-lining cells and the associated capillary. Shown also are connections between the osteocyte network, surface bone-lining cells, and the BRC. All cells in this network are connected with gap junctions, which might provide a pathway (block arrows) by which signals generated by osteocytes deep within the bone reach the surface and elicit remodeling events by OCs and OBs. Note also the potential direct physical contact between OCs and OBs, which would allow for signaling between these cells.

Figure 2. Working model for estrogen regulation of bone turnover via effects on osteocytes, osteoblasts, osteoclasts, and T-cells

The main effect of estrogen is to inhibit bone remodeling, likely via the osteocyte. Estrogen also inhibits bone resorption, principally by directs effects on osteoclasts, although effects of estrogen on osteoblast/osteocyte and T-cell regulation of osteoclasts likely also play a role. Estrogen deficiency is associated with a gap between bone resorption and bone formation, likely due to the loss of the effects of estrogen on decreasing osteoblast apoptosis, oxidative stress, osteoblastic NF-κB activity, and perhaps other, as yet undefined, mechanisms.