Estrogen Deficiency Induces Bone Loss by Enhancing T-Cell Production of TNF-a
Estrogen deficiency is known to induce bone loss by upregulating osteoclast formation, which plays a key role in bone resorption. Activated T cells also induce osteoclast formation contributing to inflammation-induced bone loss. Since T cells express estrogen receptors, Cenci, et al (J Clin Inv 106:1229, 2000) have investigated the role of T cells in ovariectomy-induced bone loss. Studies were done in athymic nude mice (T cell deficient) and control littermates. Animals were either sham operated or ovariectomized (OVX), and treated with estradiol or placebo.
Cultures of bone marrow monocytes (BMM) from OVX athymic mice did not have increased osteoclast formation when compared with sham athymic mice. In the control mice, OVX showed a 2-fold increase in osteoclast formation when compared with sham in cultures of BMM. In further studies using purified BMM and T cells, the addition of T cells from OVX mice to BMMs from either mice group increased macrophage colony-stimulating factory (M-CSF) and receptor activator of NF-kb ligand (RANKL) induced osteoclast formation and this potentiation was inhibited by the addition of TNF-a antibody. No increase in osteoclast formation was detected when this same experiment was performed with T cells from estrogen-replete mice. ELISA measurements showed that there was a 4-fold increase of TNF-ain the media from cultures of T cells from OVX mice as compared to T cells from estrogen-replete mice.
These findings demonstrate a mechanism by which estrogen prevents osteoclastic bone resorption and bone loss by suppressing TNF-aproduction from targeted T cells.
Editorial Comment: These studies demonstrate for the first time that bone loss in estrogen deficient states is mediated (at least in mice) through increased TNF-aproduction by T cells in the bone marrow. Whether this finding applies to humans or not remains to be determined. If so, anti-TNF therapy may be efficacious in treatment of osteoporosis. The study also elucidates a previously under recognized role of T cells in bone loss.