Bone Loss in Surgically Ovariectomized Premenopausal Women Is Associated With T Lymphocyte Activation and Thymic Hypertrophy

Abstract

Post-menopausal osteoporosis is associated with estrogen deficiency and rapid bone loss. The mechanism by which estrogen deficiency results in bone loss has not been fully explained. Studies in mice rendered acutely estrogen deficient by ovariectomy have suggested that estrogen deficiency results in an activated T-lymphocyte phenotype and increased production of pro-osteoclastic cytokines. The aim of this study was to translate these findings from mouse models that suggest that the T-lymphocyte plays an important role in the etiology of post-menopausal osteoporosis. We recruited pre-menopausal women who underwent ovariectomy (OVX) for benign gynecologic conditions or for prophylaxis against ovarian cancer and a group of matched control women without OVX. Subjects provided blood samples to characterize T-lymphocyte phenotype by Fluorescence-activated cell sorting (FACS) and for T-lymphocyte culture and collection of conditioned media. Bone mineral density at the lumbar spine and left femoral neck was performed annually for two years and volumetric measurements by computed tomography (CT) of the thymus were obtained during the first 6 months. We enrolled 6 OVX and 13 control women. The OVX subjects had a significant loss of bone mineral density at the lumbar spine and left femoral neck. The volumetric thymus measurements suggested an increase in thymus size in the OVX subjects but did not reach statistical significance due to the small sample size. The T-lymphocyte phenotype in the OVX subjects demonstrated increased T-lymphocyte activation by FACS compared to the control subjects. Our preliminary findings support the hypothesis that estrogen deficiency leads to an activated T-lymphocyte phenotype which may contribute to the bone loss seen in estrogen deficiency. Larger clinical studies are necessary to confirm these findings.

Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics

“…Furthermore bone loss did not occur in mice lacking T cell TNF production (37,40,54,55) or lacking the costimulatory molecule CD40L (53) or in mice treated with CTLA4-Ig, an agent that transmits an inhibitory signal to T cells (56). Clinical evidence corroborates the role of T cell-produced TNF in postmenopausal bone loss (30,31). Mechanistically, ovx induces proliferation of conventional T cells via an antigen-dependent process (56,57), thereby increasing the number of CD4 + and CD8 + T cells in the BM and enhancing their production of TNF (37,53).…”

“…Among the mechanisms responsible for the bone loss induced by surgical menopause in mice and humans is an expansion in the BM of activated T cells that produce TNF (30,31,37,40). In the mouse, this phenomenon results from enhanced thymic-dependent differentiation of BM-derived progenitors and IFNγ-driven peripheral expansion of mature T cells (57,64).…”

“…In the mouse, osteocytes are probably the most relevant source of RANKL in estrogen-deficient mice (29). In humans, estrogen deficiency is associated with an expansion of RANKL-and TNF-expressing T cells and B cells (27,28,30,31). The contributing influences of IL-1 and TNF in humans was underscored by reports showing that menopause increases the levels of both of these immune factors (32)(33)(34)(35), while treatment with TNF and IL-1 inhibitors prevents the increase in bone resorption that results from estrogen deficiency (36).…”

Osteoimmunology: from mice to humans

“…41,42 In humans the effect of estrogens on the immune function has been demonstrated in the ability to modulate T-cell cytokine production, 42,43 to answer to immune stimulation, 44 whereas OVX increases T-cell activation. 5,43 Estrogen deficiency increases the number of T cells by increasing their thymic output. It has been demonstrated in humans as well as in mice that after ovariectomy (OVX) the size of the thymus increases, and that T-cell activation is increased after OVX.…”

“…It has been demonstrated in humans as well as in mice that after ovariectomy (OVX) the size of the thymus increases, and that T-cell activation is increased after OVX. 43 In mouse models, Th17 cells have been implicated in OVXinduced bone loss. These cells increased after OVX because of the upregulation of STAT3, ROR-ct and ROR-a and downregulation of Foxp3, which antagonizes Th17-cell differentiation.…”