Search

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]

Objectives. To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS) patients by assessing the levels of fecal calprotectin, to study levels of serum calprotectin in AS, and to correlate the concentrations of calprotectin in feces and serum with reported gastrointestinal symptoms, medication, and measures of disease activity. Methods. All patients fulfilling the Modified New York criteria of AS at the study centers were invited to participate. The patients answered questionnaires concerning medication, symptoms, and disease activity. Physical examination was performed, including back mobility tests. Samples of stools and blood were collected and analyzed for fecal and serum calprotectin. Results. Elevated levels of fecal calprotectin (>50 mg/kg) was found in 140 of 205 AS patients (68%). Levels of fecal calprotectin were associated with increasing age, disease duration, ESR, CRP, and serum calprotectin, but not with gastrointestinal symptoms. Fecal calprotectin was higher in patients using NSAIDs, salicylates, and proton pump inhibitors, but lower in patients using methotrexate and infliximab. Serum calprotectin levels were normal or low in 98% of AS patients and not different from the levels in healthy blood donors. Serum calprotectin levels were positively associated with ESR, CRP, WBC, and PLT. Conclusions. Two-thirds of AS patients had elevated levels of fecal calprotectin, without associated gastrointestinal symptoms. Serum calprotectin was mostly normal in AS, in contrast to various other inflammatory rheumatic diseases. We suggest that fecal calprotectin may be a marker for subclinical intestinal inflammation in AS and should be measured after stopping NSAIDs, but further endoscopic studies are needed. [ABSTRACT FROM AUTHOR]

Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus-induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [ABSTRACT FROM AUTHOR]

Bacterial arthritis is the most rapidly progressing destructive joint disease in humans. To evaluate bone resorption and formation, mice were injected with Staphylococcus aureus and killed after 3 and 14 days. Both total and trabecular bone mineral density were, compared with those in uninfected controls, already significantly reduced 3 days after bacterial inoculation. Serum levels of type I collagen fragments were significantly increased and osteocalcin levels decreased in mice infected with S. aureus, compared with those in non-infected mice, 3 and 14 days after bacterial inoculation. This study shows that there is a rapid and easily measurable systemic bone resorption during S. aureus-induced arthritis. [ABSTRACT FROM AUTHOR]

In addition to its effects on sexual differentiation and reproduction, estrogen has important impact on the immune system and on bone. It has also been evident that the effects of estrogen on bone to a large extent are mediated via its action on immune cells. Estrogen has a dichotomous impact on the immune system by downregulation of inflammatory immune responses but simultaneous upregulation of immunoglobulin production. Consequently, immune-mediated diseases in humans and in animal models are modulated by estrogen. Estrogen deficiency after ovariectomy in mice and after menopause in women is associated with significant bone loss. In rheumatic diseases such as rheumatoid arthritis (RA), osteoporosis is frequent, and in patients with postmenopausal RA, the degree of bone loss is dramatically increased. Hormone replacement therapy (HRT) in murine and human arthritis has beneficial effects on bone loss, as expected, but it also ameliorates inflammation and inflammation-triggered joint destruction. Long-term use of HRT has been associated with increased risk of breast cancer, thrombosis, and possibly also stroke. Accordingly, there is great need for new activators of estrogen receptors (ERs) selectively reproducing only the beneficial effects of estrogen. To achieve this aim, better knowledge of the mechanisms of how activation of ER-α and ER-β modulates the immune system and bone at the cellular and molecular levels is necessary. [ABSTRACT FROM AUTHOR]

Autoimmune, lupus-prone MRL lpr/lpr mice were treated orally with oxo-quinoline-3-carboxamide (ABR-25757), a newly developed immunomodulator. Treatment was initiated in one set of experiment at the age of 10 weeks, before the onset of clinically apparent disease, and in another set at 15 weeks, after the development of established lupus disease. Beneficial therapeutic effects were obtained even when ABR-25757 was administered at the lowest dose tested (7.5 μg/mouse/week) to 15 weeks old mice with established lupus disease. The effects of ABR-25757 on longevity, as well as on development of glomerulonephritis were pronounced and comparable with those of LS-2616, a potent immunomodulator. Administration of ABR-25757 did not significantly alter T cell responses in vivo nor in vitro. In addition, it only marginally suppressed B cell responses measured as frequencies of immunoglobulin secreting cells. By the same token this compound did not affect overall leukocyte content in primary (bone marrow) or secondary (spleen) lymphoid tissues. In contrast, treatment with ABR-25757 up regulated expression of pro-inflammatory transcription factors NF-κB and AP-1. These results suggest (a) a potential therapeutic role of ABR-25757 in the treatment of experimental lupus and (b) that the effect of the treatment is mediated by immunodeviation rather than by immunosuppression. [Copyright &y& Elsevier]

Mycophenolic acid (MPA) reversibly inhibits inosine 5′-monophosphate dehydrogenase (IMPDH), an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study, MPA''s immunomodulating effects in vitro on the B cell hybridoma MAR 18.5 were investigated. The cells were exposed for MPA at either 1 or 10 μM for 24 h, and the levels of immunoglobulins, cytokines and lactate dehydrogensase in supernatants were measured. The frequency of immunoglobulin producing cells and the proliferation and viability of the cells was also investigated. MPA exposure reduced the frequency of immunoglobulin producing cells, decreased the levels of immunoglobulins and cytokines in the supernatants, and decreased the cell proliferation. MPA was slightly cytotoxic as indicated by increased lactate dehydrogenase (LDH) levels and reduced viability. All MPA-induced effects were totally reversed by the addition of guanosine to the cultures. Thus, since activated B lymphocytes play a central role in lupus and our results show that B cells are targets for MPA, we propose that direct effects on B cells may be an important mechanism for the ameliorating effects of MMF in SLE. [Copyright &y& Elsevier]

Mycophenolic acid (MPA) inhibits reversibly inosine 5′-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study MPA’s immunomodulating effects in vitro on the murine macrophage cell line IC-21 were investigated. The cells were exposed to MPA together with lipopolysaccharide and IFN-γ. Cytokine, NO2−, and lactate dehydrogenase levels in supernatants and cell lysates were analysed as well as the proliferation of IC-21 cells. MPA exposure reduced the total levels of all molecules investigated and suppressed the proliferation. All MPA-induced effects were reversed by the addition of guanosine to the cultures. Since macrophages play a role in lupus nephritis, our results indicate that modulation of macrophages may be involved in the ameliorating effects of MMF in SLE. [Copyright &y& Elsevier]

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 article presents an obituary for Andrzej Tarkowski, professor and senior consultant in Rheumatology, is presented.

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 17β-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. [ABSTRACT FROM AUTHOR]

Immunoglobulin G (IgG) is important in clearance and recognition of previously presented antigens and after activation, IgGs can interact with the Fc gamma receptors (FcγRs) on haematopoietic cells, including bone‐resorbing osteoclasts. The pathogenicity of IgG, that is the ability to elicit stimulatory effects via FcγRs, can be modulated by attachment of sugar moieties, including sialic acids. Human IgGs and autoantibodies are associated with bone loss in autoimmune disease. However, the impact of polyclonal murine IgG via FcγRs on bone loss is poorly understood. Here, we investigate if heat‐aggregated activated murine polyclonal IgG complexes have any direct effects on murine osteoclasts and if they modulate arthritis‐mediated bone loss. Using cell cultures of murine osteoclasts, we show that IgG complexes without sialic acids (de‐IgG complexes) enhance receptor activator of nuclear factor kappa‐Β ligand (RANKL)‐stimulated osteoclastogenesis, an effect associated with increased FcγRIII expression. Using an in vivo model of arthritis‐mediated bone loss, where IgG complexes were injected into arthritic knees, no effect on the severity of arthritis or the degree of arthritis‐mediated bone loss was detected. Interestingly, injection of de‐IgG complexes into non‐arthritic knees increased osteoclast formation and enhanced bone erosions. Our findings show that activated de‐IgG complexes have no additive effect on arthritis‐mediated bone loss. However, de‐IgG complexes potentiate murine osteoclastogenesis and enhance local bone erosion in non‐arthritic bones, further confirming the link between the adaptive immune system and bone. [ABSTRACT FROM AUTHOR]

Objectives To study baseline serum hepatocyte growth factor (s-HGF) as a predictor of spinal radiographic progression overall and by sex and to analyse factors correlated to changes in s-HGF in patients with AS. Methods At baseline and the 5-year follow-up, s-HGF was analysed with ELISA. Spinal radiographs were graded according to modified Stoke Ankylosing Spondylitis Spinal Score. Radiographic progression was defined as ≥2 modified Stoke Ankylosing Spondylitis Spinal Score units/5 years or development of ≥1 syndesmophyte. Logistic regression analyses were used. Results Of 204 baseline participants, 163 (80%) completed all examinations at the 5-year follow-up (54% men). Baseline s-HGF was significantly higher in men who developed ≥1 syndesmophyte compared with non-progressors, median (interquartile range) baseline s-HGF 1551 (1449–1898) vs 1436 (1200–1569) pg/ml, P   =  0.003. The calculated optimal cut-off point for baseline s-HGF ≥1520 pg/ml showed a sensitivity of 70%, a specificity of 69% and univariate odds radio (95% CI) of 5.25 (1.69, 14.10) as predictor of development of ≥1 new syndesmophyte in men. Baseline s-HGF ≥1520 pg/ml remained significantly associated with development of ≥1 new syndesmophyte in men in an analysis adjusted for the baseline variables age, smoking, presence of syndesmophytes and CRP, odds radio 3.97 (1.36, 11.60). In women, no association with HGF and radiographic progression was found. Changes in s-HGF were positively correlated with changes in ESR and CRP. Conclusion In this prospective cohort study elevated s-HGF was shown to be associated with development of new syndesmophytes in men with AS. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients. Methods: 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4+ helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT. Results: Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3+ Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3+ Th17 cells were associated with bone density or bone microarchitecture measurements. Conclusions: Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3+ Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA. [ABSTRACT FROM AUTHOR]

Women show an increased prevalence of adult-onset asthma compared to men and previous studies have shown that testosterone inhibits while estrogen worsens allergen-induced airway inflammation. However, detailed knowledge about the aggravating effects of estrogen on immune responses remain unclear. Defining the effects of physiological levels of estrogen on immune responses in asthma would aid in the development of improved treatment strategies. In this study, the importance of estrogen for the sex difference in asthma was determined using a murine model of house dust mite (HDM)-induced airway inflammation on intact female and male mice, as well as on ovariectomized (OVX) female mice treated with a physiological dose of 17β-estradiol (E2). Innate and adaptive immune responses were defined in bronchoalveolar lavage fluid, mediastinal lymph node (mLN) and lung tissue. The results reveal increased numbers of lung eosinophils, macrophages, and dendritic cells in female but not in male mice after HDM challenge. Females also exhibit higher numbers of Th17 cells in both mLN and lung in response to HDM. However, treatment of OVX mice with physiological levels of E2 does not influence any of the analyzed cell populations. Together, this study confirms the previously reported sex difference in allergen-induced airway inflammation and show that female mice mount stronger innate and adaptive immune responses to HDM challenge, but these effects are not mediated by physiological levels of E2. [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]

Aim A more vigorous immune system activation is generally seen in women as compared to men. The reasons for these differences are still not understood. By investigating the immune-regulatory role of estrogens, we have previously shown that estradiol (E2) can regulate and ameliorate rheumatoid arthritis models. The aim of this study was to elucidate the role of ovariectomy (ovx) and estradiol (E2) in innate immune responses. Methods Female mice were ovx or sham operated. After three weeks, either dorsal air pouches were established by injections of sterile air with subsequent lipopolysaccharide (LPS) injection, or LPS was injected intra-peritoneally (i.p). Mice received daily injections with E2 or vehicle for three days before challenge. 6 hours after challenge in the air pouch, blood cells were counted, leukocytes from the pouch were analyzed by flow cytometry, and cytometric bead array or ELISA were used to quantify cytokines collected from the air pouch. Blood cells were counted 1 h after i.p challenge. Results Compared to sham, blood leukocyte numbers increased after ovx and ovx+E2 6 h after LPS injections into the air pouch. LPS after ovx induced neutrophil infiltration into the pouch, accompanied by increased levels of MCP-1 and IL-6. Ovx+E2 further enhanced cell infiltration after LPS; however, the cell population diversified by also including more macrophages and monocytes, with reduced MCP-1 and IL-6 levels. Compared to ovx, blood leukocyte numbers increased already 1 h after i.p challenge in ovx+E2 mice. Conclusion Our findings suggest that ovarian hormones and estradiol can adjust the acute innate immune reaction by regulating cell recruitment to inflammatory sites, diversify the responding cell population, and at the same time down-regulate production of certain pro-inflammatory cytokines. Our results also suggest a faster responding immune system after E2. Our results bring further information into the intricate relationship between inflammation and sex steroids. [ABSTRACT FROM AUTHOR]

Background/objective 17β-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. [ABSTRACT FROM AUTHOR]

Background: Increased reactive oxygen species and estrogen deficiency contribute to the pathophysiology of postmenopausal osteoporosis. Reactive oxygen species contribute to bone degradation and is necessary for RANKLinduced osteoclast differentiation. In postmenopausal bone loss, reactive oxygen species can also activate immune cells to further enhance bone resorption. Here, we investigated the role of reactive oxygen species in ovariectomyinduced osteoporosis in mice deficient in Ncf1, a subunit for the NADPH oxidase 2 and a well-known regulator of the immune system. Methods: B10.Q wild-type (WT) mice and mice with a spontaneous point mutation in the Ncf1-gene (Ncf1*/*) were ovariectomized (ovx) or sham-operated. After 4 weeks, osteoclasts were generated ex vivo, and bone mineral density was measured using peripheral quantitative computed tomography. Lymphocyte populations, macrophages, pre-osteoclasts and intracellular reactive oxygen species were analyzed by flow cytometry. Results: After ovx, Ncf1*/*-mice formed fewer osteoclasts ex vivo compared to WT mice. However, trabecular bone mineral density decreased similarly in both genotypes after ovx. Ncf1*/*-mice had a larger population of preosteoclasts, whereas lymphocytes were activated to the same extent in both genotypes. Conclusion: Ncf1*/*-mice develop fewer osteoclasts after ovx than WT mice. However, irrespective of genotype, bone mineral density decreases after ovx, indicating that a compensatory mechanism retains bone degradation after ovx. [ABSTRACT FROM AUTHOR]

The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)α, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ERαAF-1 for the estradiol (E2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ERαAF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ERαAF-1 (ERαAF-10) with E2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-1° mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ERαAF -1 in female mice. These results could lead to development of more specific treatments for osteoporosis. [ABSTRACT FROM AUTHOR]

Objective. RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammationassociated bone loss using CIA in mice. Methods. Female DBA/1 mice were ovariectomised and subjected to CIA as a model of post-menopausal RA. Mice received treatment with LAS, BZA, 17b-estradiol (E2) as reference or vehicle. Arthritis development was assessed and BMD was determined by peripheral quantitative CT of the femurs. Serologic markers of inflammation and cartilage destruction were analysed. Immune cells in lymph nodes were studied by flow cytometry. Results. LAS and BZA reduced the clinical severity of arthritis as well as the grade of histologic synovitis and erosions on cartilage and bone. Moreover, SERMs protected against generalised bone loss in CIA by increasing trabecular BMD. Both SERMs decreased serum marker of cartilage destruction and LAS reduced serum IL-6 levels. SERMs did not alter Th17 cells in lymph nodes as E2 did. Conclusion. The anti-osteoporotic drugs LAS and BZA were found to be potent inhibitors of joint inflammation and bone destruction in experimental arthritis. This study provides new important knowledge regarding the treatment regimen of post-menopausal women with RA who suffer from increased risk for osteoporosis. [ABSTRACT FROM AUTHOR]

Interleukin-17 (IL-17) drives inflammation and destruction of joints in rheumatoid arthritis (RA). The female sex hormone 17β-estradiol (E2) inhibits experimental arthritis. γδT cells are significant producers of IL-17, thus the aim of this study was to investigate if E2 influenced IL-17 + γδT cells during arthritis development using a variety of experimental RA models: collagen-induced arthritis (CIA); antigen-induced arthritis (AIA); and collagen antibody-induced arthritis (CAIA). We demonstrate that E2 treatment decreases IL-17 + γδT cell number in joints, but increases IL-17 + γδT cells in draining lymph nodes, suggesting an E2-mediated prevention of IL-17 + γδT cell migration from lymph nodes to joints, in concert with our recently reported effects of E2 on Th17 cells (Andersson et al., 2015). E2 did neither influence the general γδT cell population nor IFNγ + γδT cells, implying a selective regulation of IL-17-producing cells. In conclusion, this study contributes to the understanding of estrogen's role in autoimmune disease. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

Objective Bone loss in arthritis is a complex process characterized by bone erosions and periarticular and generalized bone loss. The antigen-induced arthritis (AIA) model is mainly used to study synovitis and joint destruction, including bone erosions; however, periarticular bone loss has been less extensively investigated. The objectives of this study were to characterize and establish AIA as a model for periarticular bone loss, and to determine the importance of NADPH oxidase 2 (NOX-2)-derived reactive oxygen species (ROS) in periarticular bone loss. Methods Arthritis was induced in mice by local injection of antigen in one knee; the other knee was used as a nonarthritis control. At study termination, the knees were collected for histologic assessment. Periarticular bone mineral density (BMD) was investigated by peripheral quantitative computed tomography. Flow cytometric analyses were performed using synovial and bone marrow cells. Results AIA resulted in decreased periarticular trabecular BMD and increased frequencies of preosteoclasts, neutrophils, and monocytes in the arthritic synovial tissue. Arthritis induction resulted in an increased capability to produce ROS. However, induction of arthritis in Ncf1*/* mice, which lack NOX-2-derived ROS, and control mice resulted in similar reductions in periarticular trabecular BMD. Conclusion The initiation of AIA resulted in periarticular bone loss associated with local effects on inflammatory cells and osteoclasts. Furthermore, based on our observations using this model, we conclude that NOX-2-derived ROS production is not essential for inflammation-mediated periarticular bone loss. Thus, AIA can be used as a model to investigate the pathogenesis of local inflammation-mediated bone loss. [ABSTRACT FROM AUTHOR]

Background: Cardiac conduction disturbances are common in spondyloarthropathies such as ankylosing spondylitis (AS). Whether their occurrence can be linked to signs and symptoms of rheumatic disease activity is an unsettled issue addressed in this study. Methods: In this cross-sectional study patients with AS according to modified New York criteria but without psoriasis, inflammatory bowel disease, dementia, pregnancy, other severe diseases such as malignancy and difficulties in answering questionnaires were invited; and 210 participated (120 men), mean age 49 years (SD 13; range: 16-77). Questionnaires, physical examination, ECG, and laboratory tests were performed at the same visit. Results: Cardiac conduction disturbances were common and diagnosed in 10-33%, depending on if conservative or less conservative predefined criteria were applied. They consisted mostly of 1st degree atrio-ventricular block and prolonged QRS duration, but one patient had a pacemaker and 7 more had complete bundle branch blocks. Conduction abnormalities were associated mainly with age, male gender and body weight, and not with laboratory measures of inflammation or with Bath Ankylosing Spondylitis Disease Activity Index. Neither were they associated with the presence of HLA B27, which was found in 87% of all patients; the subtype B270502 dominated in all patients. Conclusions: Cardiac conduction abnormalities are common in AS, but not associated with markers of disease activity or specific B27 subtypes. Even relatively mild conduction system abnormalities might, however, indirectly affect morbidity and mortality. [ABSTRACT FROM AUTHOR]

Ovariectomy/estrogen deficiency causes selective apoptosis of the serous epithelial cells of the submandibular glands (SMG) in female mice. Because such apoptosis does not occur in healthy, estrogen-deficient male mice, it was hypothesized that dihydrotestosterone (DHT) protects epithelial SMG cells against apoptosis. The antiapoptotic effect of DHT on human epithelial HSG cells exposed to tumor necrosis factor-α and cycloheximide was studied. Correspondingly, the proapoptotic effect of androgen deficiency was studied in orchiectomized (ORX) androgenknockout (ARKO) and wild-type (WT) mice. The health state of the SMG cells was studied with Alcian blue-periodic acid Schiff (ABPAS) and amylase staining and transmission electron microscopy (TEM). The eventual protective antiapoptotic effect of dehydroepiandrosterone (DHEA) treatment was tested in this model. Apoptosis was assessed using immunohistochemisty of cleaved effector caspase-3 and its activator caspase-8 and the TUNEL assay. To test for the bioavailability, intracrine metabolism and sex steroid effects of DHEA, cystein-rich secretory protein-3 (CRISP-3), and leucine-isoleucine- valine transport system 1 (LIV-1) were used as androgen- and estrogen-regulated biomarkers, respectively. DHT protected HSG cells against induced apoptosis. In mice, androgen deficiency resulted in extensive activation of apoptotic caspase-8/3 cascade in serous epithelial cells. However, in salivary glands, active caspases were not translocated to nuclei but secreted to salivary ducts in exosome-like particles, which are associated with weak AB-PAS and amylase staining of the androgen-deprived cells and reduced number of intracellular secretory granules. DHEA treatment suppressed induction of proapoptotic caspases and almost normalized mucins and amylase and ultramophology of the serous epithelial cells in WT ORX but not ARKO ORX mice. According to the CRISP-3 and LIV-1 markers, DHEA probably exerted its effects via intracrine conversion to DHT [ABSTRACT FROM AUTHOR]

Abstract: The enzyme catechol-O-methyltransferase (COMT) is part of the metabolic pathway of 17β-estradiol, converting 2-hydroxyestradiol to 2-methoxyestradiol. We recently showed that administration of the COMT product 2-methoxyestradiol has anti-inflammatory and anti-osteoporotic effects. We have now investigated whether COMT affects the immune system, by immunologically phenotyping COMT deficient (COMT−/−) mice. Immunoglobulin production, T lymphocyte proliferation, NK cell cytotoxicity and oxygen radical production were assessed. In male COMT−/−-mice, the total number of T-, and B-lymphocytes from spleen increased but the T-cell proliferative response decreased. The NK cell population shifted toward less mature cells, leaving cytotoxic capacity unaffected. In COMT−/−-females, a higher frequency of neutrophils was found but the oxygen radical production was unaltered. In conclusion, only minor changes of the immune system were seen in COMT deficient mice, and the changes were usually seen in males. This study provides clues into how COMT activity, and hence gender differences, affects the immune system. [Copyright &y& Elsevier]

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]

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]

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease that is more common in women than in men. The peak incidence in females coincides with menopause when the ovarian production of sex hormones drops markedly. RA is characterized by skeletal manifestations where production of pro-inflammatory mediators, connected to the inflammation in the joint, leads to bone loss. Animal studies have revealed distinct beneficial effects of estrogens on arthritis, and a positive effect of hormone replacement therapy has been reported in women with postmenopausal RA. This review will focus on the influence of female sex hormones in the pathogenesis and progression of RA. [Copyright &y& Elsevier]

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.

Background: Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis. Methods: Female B10.Q-ncf1*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines. Results: Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6. Conclusions: This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA. [ABSTRACT FROM AUTHOR]

Background: The endothelin-1 (ET-1) system plays a pathophysiologic role in patients with pulmonary arterial hypertension (PAH). Results from previous studies assessing the transpulmonary gradient of ET-1 have been inconsistent. The influence of an intravenous epoprostenol infusion on the transpulmonary ET-1 gradient is unknown. Methods: In a prospective investigation, serum concentrations of ET-1 were measured in 39 consecutive patients (31 women; mean age, 20–77 years) with pulmonary hypertension (33 with PAH) and compared with 20 controls. The effect of intravenous epoprostenol administration on the transpulmonary gradient of ET-1 was analyzed in 13 patients with pulmonary hypertension. Blood samples were taken simultaneously from the pulmonary artery and radial artery. Results: The serum levels of ET-1 were significantly higher in the arterial (3.9 ± 1.28 vs 2.53 ± 0.24 pg/ml, p < 0.001) and mixed venous blood samples (3.9 ± 1.21 vs 2.52 ± 0.29 pg/ml, p < 0.001) in patients with pulmonary hypertension than in controls. The arterial/venous ratio of ET-1 in patients (1.0 ± 0.1) and in the control group (1.0 ± 0.05) was similar (p = 0.79). During intravenous epoprostenol infusion, there were no changes in the mean transpulmonary ET-1 gradient (0.98 ± 0.07 vs 0.96 ± 0.09, p = 0.52), despite significant hemodynamic changes. Conclusion: The ET-1 radial artery/pulmonary artery ratio of unity indicates a balanced release and clearance of ET-1 across the lung circulation in controls and in patients with different forms of pulmonary hypertension. ET-1 levels across the pulmonary circulation did not change during epoprostenol infusion. [Copyright &y& Elsevier]

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.

Environmental factors are thought to play a major role in the development of rheumatoid arthritis. Because the use of ethanol is widespread, we assessed the role of ethanol intake on the propensity to develop chronic arthritis. Collagen type II-immunized mice were given water or water containing 10% (vol/vol) ethanol or its metabolite acetaldehyde. Their development of arthritis was assessed, as well as the impact of ethanol on leukocyte migration and activation of intracellular transcription factors. Mice exposed daily to this dose of ethanol did not display any liver toxicity, and the development of erosive arthritis was almost totally abrogated. In contrast, the antibody-mediated effector phase of collagen-induced arthritis was not influenced by ethanol exposure. Also, the major ethanol metabolite, acetaldehyde, prevented the development of arthritis. This antiinflammatory and antidestructive property of ethanol was mediated by (i) down-regulation of leukocyte migration and (ii) up-regulation of testosterone secretion, with the latter leading to decreased NF-κB activation. We conclude that low but persistent ethanol consumption delays the onset and halts the progression of collagen-induced arthritis by interaction with innate immune responsiveness. [ABSTRACT FROM AUTHOR]

Background: Estrogens and androgens have extensive effects on the immune system, for example they suppress both T and B lymphopoiesis in thymus and bone marrow. Submandibular glands are sexually dimorphic in rodents, resulting in larger granular convoluted tubules in males compared to females. The aim of the present experiments was to investigate the estrogenic and androgenic effects of 4-estren-3 α ,17β-diol (estren) on thymus, bone marrow and submandibular glands, and compare the effects to those of 17β-estradiol (E2) and 5 α -dihydrotestosterone (DHT), respectively. Estrogen receptors (ERs) were blocked by treatment of mice with the ER-antagonist ICI 182,780; also, knock-out mice lacking one or both ERs were used. Results: As expected, the presence of functional ERs was mandatory for all the effects of E2. Similar to DHT-treatment, estren-treatment resulted in decreased thymus weight, as well as decreased frequency of bone marrow B cells. Treatment with estren or DHT also resulted in a shift in submandibular glands towards an androgen phenotype. All the effects of estren and DHT were independent of ERs. Conclusion: Our study is the first to show that estren has similar effects as the androgen DHT on lymphopoiesis in thymus and bone marrow, and on submandibular glands, and that these effects are independent of estrogen receptors. This supports the hypothesis of estren being able to signal through the androgen receptor. [ABSTRACT FROM AUTHOR]

The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents. [ABSTRACT FROM AUTHOR]

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.

Background: Cardiac conduction disturbances are common in spondyloarthropathies such as ankylosing spondylitis (AS). Whether their occurrence can be linked to signs and symptoms of rheumatic disease activity is an unsettled issue addressed in this study.Methods: In this cross-sectional study patients with AS according to modified New York criteria but without psoriasis, inflammatory bowel disease, dementia, pregnancy, other severe diseases such as malignancy and difficulties in answering questionnaires were invited; and 210 participated (120 men), mean age 49 years (SD 13; range: 16-77). Questionnaires, physical examination, ECG, and laboratory tests were performed at the same visit.Results: Cardiac conduction disturbances were common and diagnosed in 10-33%, depending on if conservative or less conservative predefined criteria were applied. They consisted mostly of 1st degree atrio-ventricular block and prolonged QRS duration, but one patient had a pacemaker and 7 more had complete bundle branch blocks. Conduction abnormalities were associated mainly with age, male gender and body weight, and not with laboratory measures of inflammation or with Bath Ankylosing Spondylitis Disease Activity Index. Neither were they associated with the presence of HLA B27, which was found in 87% of all patients; the subtype B270502 dominated in all patients.Conclusions: Cardiac conduction abnormalities are common in AS, but not associated with markers of disease activity or specific B27 subtypes. Even relatively mild conduction system abnormalities might, however, indirectly affect morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.Methods: Female B10.Q-ncf1*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines.Results: Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6.Conclusions: This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA. [ABSTRACT FROM AUTHOR]