| 1. |
- Engdahl, Cecilia, 1983, et al.
(författare)
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Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor alpha, and not estrogen receptor beta or G protein-coupled receptor 30.
- 2010
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Ingår i: Arthritis and rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:2, s. 524-33
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ERalpha or ERbeta or via the recently proposed transmembrane estrogen receptor G protein-coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA). METHODS: Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen-induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ERalpha), diarylpropionitrile (DPN; for ERbeta), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting. RESULTS: Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment. CONCLUSION: In a well-established model of postmenopausal RA, ERalpha, but not ERbeta or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA.
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| 2. |
- Engdahl, Cecilia, 1983, et al.
(författare)
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In Vivo activation of gene transcription via estrogen response elements by raloxifene analogue.
- 2009
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Ingår i: The Journal of endocrinology. - 1479-6805.
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Tidskriftsartikel (refereegranskat)abstract
- Raloxifene is a selective estrogen receptor modulator (SERM) with tissue-specific effects. The mechanisms behind the effects of raloxifene are partly unclear and the aim of the present study was to investigate if raloxifene can activate the classical estrogen signalling pathway in vivo in three known estrogen-responsive organs, uterus (reproductive organ), bone (non-reproductive organ) and thymus (immune organ). For this purpose we have used reporter mice with a luciferase gene under control of estrogen responsive elements (EREs), enabling detection of in vivo activation of gene transcription via the classical estrogen pathway. Three-month-old ovariectomized ERE-luciferase mice were treated with the raloxifene analogue (LY117018), estradiol or vehicle for three weeks. Luciferase activation was measured in bone, uterus and thymus, and compared to bone parameters, and uterus and thymus weights. The raloxifene analogue affected bone mineral density to the same extent as estradiol, and both treatments resulted in increased luciferase activity in bone. As expected, estradiol treatment resulted in increased uterus weight and increased uterine luciferase activity, while the effect of LY117018 on uterus weight and luciferase activity was modest and significantly lower than the effect of estradiol. LY117018 and estradiol treatment resulted in similar luciferase activation in thymus. However, only estradiol treatment resulted in thymic atrophy while no effect on thymus weight was seen after LY117018 treatment. In summary, the raloxifene analogue LY117018 can activate the classical estrogen pathway in bone, uterus and thymus in vivo, and this activation is associated with bone mineral density and uterus weight, but not thymus weight.
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| 3. |
- Grahnemo, Louise, et al.
(författare)
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Possible role of lymphocytes in glucocorticoid-induced increase in trabecular bone mineral density.
- 2015
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 224:1, s. 97-108
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with anti-inflammatory glucocorticoids is associated with osteoporosis. Many of the treated patients are postmenopausal women, who even without treatment have an increased risk of osteoporosis. Lymphocytes have been shown to play a role in postmenopausal and arthritis-induced osteoporosis, and they are targeted by glucocorticoids. The aim of this study was to investigate the mechanisms behind effects of glucocorticoids on bone during health and menopause, focusing on lymphocytes. Female C57BL/6 or SCID mice were therefore sham-operated or ovariectomized and 2 weeks later treatment with dexamethasone (dex), the nonsteroidal anti-inflammatory drug carprofen, or vehicle was started and continued for 2.5 weeks. At the termination of experiments, femurs were phenotyped using peripheral quantitative computed tomography and high-resolution micro-computed tomography, and markers of bone turnover were analyzed in serum. T and B lymphocyte populations in bone marrow and spleen were analyzed by flow cytometry. Dex-treated C57BL/6 mice had increased trabecular bone mineral density, but lower cortical content and thickness compared with vehicle-treated mice. The dex-treated mice also had lower levels of bone turnover markers and markedly decreased numbers of spleen T and B lymphocytes. In contrast, these effects could not be repeated when mice were treated with the nonsteroidal anti-inflammatory drug carprofen. In addition, dex did not increase trabecular bone in ovariectomized SCID mice lacking functional T and B lymphocytes. In contrast to most literature, the results from this study indicate that treatment with dex increased trabecular bone density, which may indicate that this effect is associated with corticosteroid-induced alterations of the lymphocyte populations.
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| 4. |
- Islander, Ulrika, 1975, et al.
(författare)
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Combined treatment with Dexamethasone and Raloxifene totally abrogates osteoporosis and joint destruction in experimental postmenopausal arthritis
- 2011
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Postmenopausal patients with rheumatoid arthritis (RA) are often treated with corticosteroids. Loss of estrogen, the inflammatory disease and exposure to corticosteroids all contribute to the development of osteoporosis. Therefore, our aim was to investigate if addition of the selective estrogen receptor modulator raloxifene, or estradiol, could prevent loss of bone mineral density in ovariectomized and dexamethasone treated mice with collagen-induced arthritis (CIA). Methods: Female DBA/1-mice were ovariectomized or sham-operated, and CIA was induced. Treatment with dexamethasone (Dex) (125 microg/d), estradiol (E2) (1 microg/d) or raloxifene (Ral) (120 microg/day) alone, or the combination of Dex + E2 or Dex + Ral, was started after disease onset, and continued until termination of the experiments. Arthritic paws were collected for histology and one of the femoral bones was used for measurement of bone mineral density. Results: Dex-treatment alone protected against arthritis and joint destruction, but had no effect on osteoporosis in CIA. However, additional treatment with either Ral or E2 resulted in completely preserved bone mineral density. Conclusions: Addition of raloxifene or estradiol to dexamethasone-treatment in experimental postmenopausal polyarthritis prevents generalized bone loss.
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| 5. |
- Islander, Ulrika, 1975, et al.
(författare)
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Estren-mediated inhibition of T lymphopoiesis is estrogen receptor-independent whereas its suppression of T cell-mediated inflammation is estrogen receptor-dependent
- 2005
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Ingår i: Clin Exp Immunol. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 139:2, s. 210-5
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen has extensive effects on the immune system. The aim of the present experiments was to compare the effects of 17beta-estradiol (E2) and 4-estren-3alpha,17beta-diol (estren) on T lymphopoiesis and T cell-dependent inflammation. In order to investigate the role of estrogen receptors (ER) in the effects of E2 and estren on the immune system, ER knock-out mice lacking both ERalpha and ERbeta (DERKO) were used. T lymphopoiesis and T cell-dependent inflammation were studied by investigating thymus cellularity, the delayed-type hypersensitivity (DTH) reaction, CD4(+) T cells in spleen and serum levels of interleukin (IL)-6. As expected, the presence of ERs was mandatory for all the effects of E2. In contrast, treatment with estren reduced thymus cellularity in ER knock-out mice, indicating an effect through ER-independent pathways. Interestingly, estren suppressed only DTH, the frequency of CD4(+) T cells in spleen and serum levels of IL-6 in wild-type (WT) mice, but not in mice lacking ERs. Thus, our study is the first to show that estren inhibits T lymphopoiesis via ER-independent pathways, whereas its suppressive effects on inflammation are ER-dependent.
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| 6. |
- Islander, Ulrika, 1975, et al.
(författare)
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Estren promotes androgen phenotypes in primary lymphoid organs and submandibular glands
- 2005
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Ingår i: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- 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-3alpha,17beta-diol (estren) on thymus, bone marrow and submandibular glands, and compare the effects to those of 17beta-estradiol (E2) and 5alpha-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.
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| 7. |
- Islander, Ulrika, 1975, et al.
(författare)
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Estrogens in rheumatoid arthritis; the immune system and bone
- 2011
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 335:1, s. 14-29
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Forskningsöversikt (refereegranskat)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.
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| 8. |
- Jochems, Caroline, 1973, et al.
(författare)
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Effects of oestradiol and raloxifene on the induction and effector phases of experimental postmenopausal arthritis and secondary osteoporosis
- 2011
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Ingår i: Clinical and Experimental Immunology. - Chichester : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 165:1, s. 121-129
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Tidskriftsartikel (refereegranskat)abstract
- Oestradiol and the selective oestrogen receptor modulator (SERM) raloxifene have been shown to ameliorate collagen-induced arthritis (CIA) in rats and in mice. One aim was to investigate if raloxifene exerts its anti-arthritic and anti-osteoporotic effects during the induction or effector phase of arthritis. A second aim was to analyse if raloxifene activates the oestrogen response element (ERE) to produce its immune-modulator effects. CIA or collagen-antibody-induced arthritis (CAIA) was induced in ovariectomized DBA/1-mice. CIA was used for evaluation of treatment during the induction, and CAIA for the effector phase of arthritis and osteoporosis development. Raloxifene, oestradiol or vehicle was administered 5 days/week. The clinical disease was evaluated continuously. Bone marrow density (BMD) was analysed with peripheral quantitative computer tomography, paws were collected for histological examination, and sera were analysed for markers of bone and cartilage turnover and proinflammatory cytokines. Transgenic luciferase (Luc)-ERE mice were immunized with collagen (CII), and after 10 days injected once with raloxifene, oestradiol or vehicle before termination. Spleens were analysed for luciferase activity to measure ERE activation. Treatment with oestradiol or raloxifene during the induction phase of CIA failed to affect arthritis. Raloxifene did not hamper disease activity in CAIA, whereas oestradiol delayed the onset and ameliorated the severity. Both raloxifene and oestradiol preserved BMD in CAIA. CII-immunization increased the oestradiol-induced ERE activation in spleen, and raloxifene activated the ERE at about 25% the intensity of oestradiol. Further experiments are needed to elucidate the exact mechanisms behind this finding.
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| 9. |
- Jochems, Caroline, 1973
(författare)
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Estrogen and raloxifene in experimental arthritis and osteoporosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACT In postmenopausal rheumatoid arthritis (RA), both the estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. This leads to an increased risk of fracture, with high morbidity and mortality. More than 50% of women with postmenopausal RA suffer from osteoporosis. Hormone replacement therapy (HRT) is used to treat postmenopausal osteoporosis. HRT has also been shown to ameliorate RA, with decreased joint destruction, reduced inflammation, increased bone density and better patient health assessment. Unfortunately, longterm hormonal treatment is associated with severe side effects, and is no longer recommended. The aims of this thesis were to establish a murine model for studies of osteoporosis in postmenopausal RA. To investigate the relative contributions of estrogen deficiency and inflammation to osteoporosis development in arthritic disease. To examine whether treatment with raloxifene, a selective estrogen receptor modulator, would have the same beneficial anti-arthritic and anti-osteoporotic effects as estrogen. Furthermore, we wanted to compare the mechanisms for these effects between estrogen and raloxifene. We found that lack of endogenous estrogen and arthritic disease contributed equally and additively to osteoporosis development in collagen-induced arthritis, a murine model of human RA. Arthritic ovariectomized mice lost 55% of their trabecular bone mineral density (BMD) compared with cycling healthy mice. Raloxifene potently decreased the frequency and severity of arthritis, protected the joints from erosions, and preserved the BMD. These effects were sustained when treatment was given both as prophylaxis and in established disease, and during longterm treatment. Raloxifene down-regulated the expression of TNF? and RANKL mRNA in the spleen. These molecules are important mediators of bone loss after menopause and in RA. In contrast to estrogen, raloxifene did not affect the effector phase of the disease, as demonstrated in collagen-antibody induced arthritis. Many estrogenic effects are mediated via the classical estrogen receptors and binding to the estrogen response elements, which regulate gene transcription. We found that raloxifene activated this pathway at 1/4 of the intensity of estrogen. In conclusion, our results show that estrogen deficiency and inflammation contribute equally to bone loss in arthritis. Furthermore, raloxifene has potent anti-arthritic and anti-osteoporotic effects, and is possibly a valuable addition to conventional treatment of postmenopausal RA. Key words: rheumatoid arthritis, osteoporosis, estrogen, raloxifene, mice ISBN 978-91-628-7409-4
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| 10. |
- Jochems, Caroline, 1973, et al.
(författare)
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Long-term anti-arthritic and anti-osteoporotic effects of raloxifene in established experimental postmenopausal polyarthritis.
- 2008
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 1365-2249 .- 0009-9104. ; 152:3, s. 593-7
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Tidskriftsartikel (refereegranskat)abstract
- Both oestrogen deficiency and the inflammatory disease contribute to the generalized bone loss seen in postmenopausal rheumatoid arthritis (RA). Oestradiol and the selective oestrogen receptor modulator raloxifene have been shown to ameliorate the disease in collagen-induced arthritis (CIA), a well-established animal model for human RA. The aim of this study was to investigate whether raloxifene-treatment would be beneficial in long-term treatment of established CIA, both regarding anti-arthritic and anti-osteoporotic properties. Female dilute brown agouti mice were ovariectomized and CIA was induced. Raloxifene or vehicle treatment was administered 5 days per week, and the clinical arthritis score was evaluated continuously. At termination, bone mineral density was analysed, paws were collected for histological examination and sera were analysed for markers of bone and cartilage turnover, as well as antibodies to type II collagen and levels of interleukin (IL)-6. Treatment with raloxifene is beneficial in long-term treatment of established CIA. It hampers the disease severity and frequency, protects the joints from destruction and protects against the development of osteoporosis. The proinflammatory cytokine IL-6 was down-regulated in raloxifene-treated mice compared with controls. The serum levels of antibodies to collagen were not affected by raloxifene-treatment. Long-term treatment with raloxifene has both anti-arthritic and anti-osteoporotic effects in established experimental postmenopausal polyarthritis.
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