Search

Women are more prone to develop rheumatoid arthritis, with peak incidence occurring around menopause. Estrogen has major effects on the immune system and is protective against arthritis. We have previously shown that treatment with estrogen inhibits inflammation and joint destruction in murine models of arthritis, although the mechanisms involved remain unclear. Fibroblastic reticular cells (FRCs) are specialized stromal cells that generate the three‐dimensional structure of lymph nodes (LNs). FRCs are vital for coordinating immune responses from within LNs and are characterized by the expression of the chemokine CCL19, which attracts immune cells. The aim of this study was to determine whether the influence of estrogen on innate and adaptive immune cells in arthritis is mediated by estrogen signaling in FRCs. Conditional knockout mice lacking estrogen receptor α (ERα) in CCL19‐expressing cells (Ccl19‐CreERαfl/fl) were generated and tested. Ccl19‐CreERαfl/fl mice and littermate controls were ovariectomized, treated with vehicle or estradiol and subjected to the 28‐day‐long antigen‐induced arthritis model to enable analyses of differentiated T‐ and B‐cell populations and innate cells in LNs by flow cytometry. The results reveal that while the response to estradiol treatment in numbers of FRCs per LN is significantly reduced in mice lacking ERα in FRCs, estrogen does not inhibit joint inflammation or markedly affect immune responses in this arthritis model. Thus, this study validates the Ccl19‐CreERαfl/fl strain for studying estrogen signaling in FRCs within inflammatory diseases, although the chosen arthritis model is deemed unsuitable for addressing this question. [ABSTRACT FROM AUTHOR]

The incidence of rheumatoid arthritis (RA) increases at the same time as menopause when estrogen level decreases. Estrogen treatment is known to reduce the IgG pathogenicity by increasing the sialylation grade on the terminal glycan chain of the Fc domain, inhibiting the binding ability to the Fc gamma receptor. Therefore, treatment with estrogen may be beneficial in pre-RA patients who have autoantibodies and are prone to get an autoimmune disease. However, estrogen treatment is associated with negative side effects, therefore selective estrogen receptor modulators (SERMs) have been developed that have estrogenic protective effects with minimal side effects. In the present study, we investigated the impact of the SERM bazedoxifene on IgG sialylation as well as on total serum protein sialylation. C57BL6 mice were ovariectomized to simulate postmenopausal status, followed by ovalbumin immunization, and then treated with estrogen (estradiol), bazedoxifene, or vehicle. We found that estrogen treatment enhanced IgG levels and had a limited effect on IgG sialylation. Treatment with bazedoxifene increased the sialic acids in plasma cells in a similar manner to E2 but did not reach statistical significance. However, we did not detect any alteration in IgG-sialylation with bazedoxifene treatment. Neither estrogen nor bazedoxifene showed any significant alteration in serum protein sialylation but had a minor effect on mRNA expression of glycosyltransferase in the bone marrow, gonadal fat, and liver. [ABSTRACT FROM AUTHOR]

Apart from the role of sex steroids in reproduction, sex steroids are also important regulators of the immune system. 17β-estradiol (E2) represses T and B cell development, but augments B cell function, possibly explaining the different nature of immune responses in men and women. Both E2 and selective estrogen receptors modulators (SERM) act via estrogen receptors (ER). Activating functions (AF)-1 and 2 of the ER bind to coregulators and thus influence target gene transcription and subsequent cellular response to ER activation. The importance of ERαAF-1 and AF-2 in the immunomodulatory effects of E2/SERM has previously not been reported. Thus, detailed studies of T and B lymphopoiesis were performed in ovariectomized E2-, lasofoxifeneor raloxifene-treated mice lacking either AF-1 or AF-2 domains of ERα, and their wildtype littermate controls. Immune cell phenotypes were analyzed with flow cytometry. All E2 and SERM-mediated inhibitory effects on thymus cellularity and thymic T cell development were clearly dependent on both ERαAFs. Interestingly, divergent roles of ERαAF-1 and ERαAF-2 in E2 and SERM-mediated modulation of bone marrow B lymphopoiesis were found. In contrast to E2, effects of lasofoxifene on early B cells did not require functional ERαAF-2, while ERαAF-1 was indispensable. Raloxifene reduced early B cells partly independent of both ERαAF-1 and ERαAF-2. Results from this study increase the understanding of the impact of ER modulation on the immune system, which can be useful in the clarification of the molecular actions of SERMs and in the development of new SERM. [ABSTRACT FROM AUTHOR]

The effects of estrogen on bone is mainly mediated via estrogen receptor (ER)ɑ. ERɑ in osteoclasts (hematopoietic origin) is involved in the trabecular bone sparing effects of estrogen but conflicting data is reported on the role of ERɑ in osteoblast lineage cells (non-hematopoietic origin) for bone metabolism. As Cre-mediated cell-specific gene inactivation, used in previous studies, might be confounded by non-specific and/or incomplete cell-specific ERɑ deletion, we herein used an alternative approach to determine the relative importance of ERɑ in hematopoietic (HC) and non-hematopoietic cells (NHC) for bone mass. Chimeric mice with selective inactivation of ERɑ in HC or NHC were created by bone marrow transplantations of wild-type (WT) and ERɑ knock-out (ERɑ-/-) mice. Estradiol treatment increased both trabecular and cortical bone mass in ovariectomized WT/WT (defined as recipient/donor) and WT/ERɑ-/- mice but not in ERɑ-/-/WT or ERɑ-/-/ERɑ-/- mice. However, estradiol effects on both bone compartments were reduced (~50%) in WT/ERɑ-/- mice compared to WT/WT mice. The effects of estradiol on fat mass and B lymphopoiesis required ERɑ specifically in NHC and HC, respectively. In conclusion, ERɑ in NHC is required for the effects of estrogen on both trabecular and cortical bone but these effects are enhanced by ERɑ in HC. [ABSTRACT FROM AUTHOR]

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor (ER) α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. It was recently demonstrated that the ER antagonist ICI 182,780 (ICI) acts as an ER agonist in uterus of mice with mutations in the ERα AF-2. To evaluate the estrogen-like effects of ICI in different tissues, ovariectomized wild-type mice and mice with mutations in the ERα AF-2 (ERαAF-20) were treated with ICI, estradiol, or vehicle for 3 wk. Estradiol increased the trabecular and cortical bone mass as well as the uterine weight, whereas it reduced fat mass, thymus weight, and the growth plate height in wild-type but not in ERαAF-20 mice. Although ICI had no effect in wild-type mice, it exerted tissue-specific effects in ERαAF-20 mice. It acted as an ERα agonist on trabecular bone mass and uterine weight, whereas no effect was seen on cortical bone mass, fat mass, or thymus weight. Surprisingly, a pronounced inverse agonistic activity was seen on the growth plate height, resulting in enhanced longitudinal bone growth. In conclusion, ICI uses ERα AF-1 in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist. [ABSTRACT FROM AUTHOR]

It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-α (ERα) expression for bone mass. Nestin-Cre mice were crossed with ERαflox mice to generate mice lacking ERα expression specifically in nervous tissue (nestin-ERα-/-). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ERα-/- mice compared with controls. Femoral bone strength was increased in nestin-ERα-/- mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ERα-/- mice was mainly caused by increased bone formation. Serum leptin levels were elevated as a result of increased leptin expression in white adipose tissue (WAT) and slightly increased amount of WAT in nestin-ERα-/- mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ERα signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ERα actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ERα-/- mice is mediated via decreased central leptin sensitivity and thereby increased secretion of leptin from WAT, which, in turn, results in increased peripheral leptin-induced bone formation. [ABSTRACT FROM AUTHOR]

The article presents a study regarding the role of nuclear estrogen receptors (ERs) in improving the effects of estrogen on arthritis and bone loss with the use of a postmenopausal rheumatoid arthritis (RA) model. It says that estrogens are main regulators of skeletal growth; thus, its deprivation reduces trabecular bone mineral density (BMD). The study analyzes the BMD of female mice which underwent ovariectomy. The results show that the postmenopausal model can improve treatment of RA.

The article presents a study which tested the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and osteoporosis using a mouse model of human rheumatoid arthritis (RA). The researchers found that in a well-established model of post-menopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen.

Presents a study which investigated the role of oestrogen receptors alpha and beta on the development of the immune system. Materials and methods; Results; Discussion.

Abstract: In postmenopausal rheumatoid arthritis, both the inflammatory disease and estrogen deficiency contribute to the development of osteoporosis. As hormone replacement therapy is no longer an option, we hypothesized that 2-methoxyestradiol (2me2) could be beneficial, and asked if such therapy was associated with effects on reproductive organs. Mice were ovariectomized and arthritis was induced, whereafter mice were administered 2me2, estradiol, or placebo. Clinical and histological scores of arthritis, together with bone mineral density were evaluated. Uteri weight, reactive oxygen species (ROS) from spleen cells, and characterization of cells from joints and lymph nodes were analyzed. In addition, in vivo activation of estrogen response elements (ERE) by 2me2 was evaluated. Treatment with 2me2 and estradiol decreased the frequency and severity of arthritis and preserved bone. Joint destruction was reduced, neutrophils diminished and ROS production decreased. The uterine weight increased upon long-term 2me2 exposure, however short-term exposure did not activate ERE in vivo. [Copyright &y& Elsevier]