A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus.

Osteoporosis is a common secondary complication in patients with systemic lupus erythematosus (SLE). Current osteoporosis treatment with bisphosphonates has some negative side effects and there is a lack of data regarding newer treatments options for SLE associated osteoporosis. The tissue-selective estrogen complex (TSEC) containing conjugated estrogens and the selective estrogen receptor modulator bazedoxifene (Bza) is approved for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis. However, it has not been evaluated for treatment of osteoporosis in postmenopausal SLE patients. Ovariectomized MRL/lpr mice constitute a model for postmenopausal lupus that can be used for osteoporosis studies. We used this model in a set of experiments where the mice were treated with different doses of 17ß-estradiol-3-benzoate (E2), Bza, or TSEC (E2 plus Bza), administered in the early or late phases of disease development. The skeleton was analyzed by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and high-resolution microcomputed tomography. The lupus disease was assessed by determination of proteinuria, hematuria, and lupus disease markers in serum. Treatment with medium dose TSEC administered in early disease protected ovariectomized MRL/lpr mice from trabecular bone loss, while there were no differences in lupus disease parameters between treatments. This is the first experimental study to investigate TSEC as a potential new therapy for osteoporosis in postmenopausal SLE.

Impact of estrogen on IgG glycosylation and serum protein glycosylation in a murine model of healthy postmenopause.

Introduction: The glycosylation of immunoglobulin (Ig) G regulates IgG interaction capability with Fc gamma receptors found in all immune cells. In pathogenic conditions, estrogen can impact IgG levels and glycosylation. Following menopause, when estrogen levels decline affecting the immune system and potentially leading to a heightened susceptibility of immune activation. Purpose: In this study, we aim to determine if estrogen levels can regulate IgG glycosylation in postmenopausal healthy situations. Methods: Mice were ovariectomized to simulate an estrogen-deficient postmenopausal status and then treated with 17-beta-estradiol (E2) at different doses and different administration strategies. Results: Using a highly sensitive liquid chromatography-tandem mass spectrometry (MS/MS) glycoproteomic method, we demonstrated that E2 treatment increased the degree of glycosylation on IgG-Fc with both galactosylation and sialylation in the position required for interaction with Fc gamma receptors. We also observed that only long-term estrogen deficiency reduces IgG levels and that estrogen status had no impact on total IgG sialylation on both Fab and Fc domains or general glycoprotein sialylation evaluated by ELISA. Furthermore, E2 status did not affect the total sialic acid content of total cells in lymphoid organs and neither B cells nor plasma cells. Conclusion: The study concluded that E2 treatment does not affect total serum glycoprotein sialylation but alters IgG glycosylation, including IgG sialylation, implying that estrogen functions as an intrinsic modulator of IgG sialylation and could thereby be one pathway by which estrogen modulates immunity.

Reduction of Mature B Cells and Immunoglobulins Results in Increased Trabecular Bone.

Inflammation has a significant effect on bone remodeling and can result in bone loss via increased stimulation of osteoclasts. Activated immunoglobulins, especially autoantibodies, can increase osteoclastogenesis and are associated with pathological bone loss. Whether immunoglobulins and mature B lymphocytes are important for general bone architecture has not been completely determined. Here we demonstrate, using a transgenic mouse model, that reduction of mature B cells and immunoglobulins leads to increased trabecular bone mass compared to wild-type (WT) littermate controls. This bone effect is associated with a decrease in the number of osteoclasts and reduced bone resorption, despite decreased expression of osteoprotegerin. We also demonstrate that the reduction of mature B cells and immunoglobulins do not prevent bone loss caused by estrogen deficiency or arthritis compared to WT littermate controls. In conclusion, the reduction of mature B cells and immunoglobulins results in disturbed regulation of trabecular bone turnover in healthy conditions but is dispensable for pathological bone loss. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effects of a tissue-selective estrogen complex on B lymphopoiesis and B cell function.

BACKGROUND/OBJECTIVE: 17ß-estradiol (E2) has major effects on the immune system. It induces thymic atrophy, inhibits both T and B lymphopoiesis and stimulates antibody production treatment with E2 has protective effects on the skeleton but is associated with negative side effects in reproductive organs. A tissue-selective estrogen complex (TSEC) comprise of estrogens combined with a selective estrogen receptor modulator (SERM). TSEC therapy displays the bone-protective effects of estrogen, while the negative side effects on reproductive organs are blocked by the SERM. In a recent publication we showed that treatment with the TSEC E2+bazedoxifene (bza) potently inhibits experimental arthritis and associated osteoporosis. In order to elucidate immunological mechanisms involved in those effects, the aim of this study was to investigate how E2+bza treatment affects the healthy immune system. METHODS: Ovariectomized C57BL/6N mice were treated with vehicle, E2, bza or E2+bza. Weights of uterus and thymus were determined and fluorescence-activated cell sorting was used to analyze B cell populations in bone marrow and spleen. Immunoglobulin production from B cells in bone marrow and spleen were determined using ELISPOT. RESULTS: Addition of bza to E2-treatment totally antagonized the E2-mediated proliferative effect on uterus. On the contrary, addition of bza to E2-treatment did not block the E2-induced thymic atrophy or inhibition of B lymphopoiesis, and did not block the E2-induced increase in immunoglobulin secretion from bone marrow B cells. CONCLUSIONS: Addition of bza to E2-treatment blocks E2-induced uteroproliferation but does not alter E2-mediated effects on thymus, B lymphopoiesis or B cell function.