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The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells. [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.

Lasofoxifene (las) and bazedoxifene (bza) are third generation selective estrogen receptor modulators (SERMs) with minimal estrogenic side effects, approved for treatment of postmenopausal osteoporosis. T cells are involved in the pathology of postmenopausal osteoporosis and previous studies have established an important role for 17β-estradiol (E2) in T cell development and function. E2 causes a drastic thymic atrophy, alters the composition of thymic T cell populations, and inhibits T cell dependent inflammation. In contrast, the second generation SERM raloxifene (ral) lacks these properties. Although las and bza are drugs approved for treatment of postmenopausal bone loss, it is of importance to study their effects on other biological aspects in order to extend the potential use of these compounds. Therefore, the aim of this study was to investigate if treatment with las and bza affects T lymphopoiesis and T cell dependent inflammation. C57Bl6 mice were ovariectomized (ovx) and treated with vehicle, E2, ral, las or bza. As expected, E2 reduced both thymus weight and decreased the proportion of early T cell progenitors while increasing more mature T cell populations in the thymus. E2 also suppressed the T cell dependent delayed-type hypersensitivity (DTH) reaction to oxazolone (OXA). Ral and las, but not bza, decreased thymus weight, while none of the SERMs had any effects on T cell populations in the thymus or on inflammation in DTH. In conclusion, this study shows that treatment with las or bza does not affect T lymphopoiesis or T cell dependent inflammation. [ABSTRACT FROM AUTHOR]

Abstract: 2-methoxyestradiol (2me2), a metabolite of 17β-estradiol (E2), has been tested in phase II clinical cancer trials and models of inflammation. Its effects are only partly clarified. We investigated the effects of 2me2 on the immune system, using ovariectomized or sham-operated mice treated with a high and a low dose of 2me2 (2me2H and 2me2L), E2 or vehicle. We investigated antagonism of tissue proliferation and estrogen response element (ERE) activation. Established immunomodulation by E2 was reproduced. 2me2L increased NK and T-cells from bone marrow, spleen and liver. Both 2me2H and E2 induced uterus proliferation in ovariectomized mice, but no antagonistic effects on uteri growth were seen in intact animals. Both E2 and 2me2H activated EREs. Immunomodulation by 2me2 is tissue-, and concentration dependent. E2 regulated the immune system more potently. The higher dose of 2me2 resulted in E2 like effects, important to consider when developing 2me2 as a drug. [Copyright &y& Elsevier]