| 1. |
- Engdahl, Cecilia, 1983, et al.
(author)
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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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In: Arthritis and rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:2, s. 524-33
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Journal article (peer-reviewed)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.
(author)
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In Vivo activation of gene transcription via estrogen response elements by raloxifene analogue.
- 2009
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In: The Journal of endocrinology. - 1479-6805.
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Journal article (peer-reviewed)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. |
- Gottschalk, Ingo, et al.
(author)
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Immobilised biomembrane affinity chromatography for binding studies of membrane proteins
- 2002
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In: Journal of chromatography. B. - 1570-0232 .- 1873-376X. ; 768:1, s. 31-40
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Research review (peer-reviewed)abstract
- Analyses of specific interactions between solutes and a membrane protein can serve to characterize the protein. Frontal affinity chromatography of an interactant on a column containing the membrane protein immobilized in a lipid environment is a simple and robust approach for series of experiments with particular protein molecules. Regression analysis of the retention volumes at a series of interactant concentrations shows the affinity of the protein for the interactant and the amount of active binding sites. The higher the affinity, the fewer sites are required to give sufficient retention. Competition experiments provide the affinities of even weakly binding solutes and the non-specific retention of the primary interactant. Hummel and Dreyer size-exclusion chromatography allows complementary analyses of non-immobilized membrane materials. Analyses of the human facilitative glucose transporter GLUT1 by use of the inhibitor cytochalasin B (radioactively labeled) and the competitive substrate D-glucose (non-labeled) showed that GLUT1 interconverted between two states, exhibiting one or two cytochalasin B-binding sites per two GLUTI monomers, dependent on the membrane composition and environment. Similar analyses of a nucleoside transporter, a photosynthetic reaction center, nicotinic acetylcholine receptors and a P-glycoprotein, alternative techniques, and immobilized-liposome chromatographic approaches are presented briefly.
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| 4. |
- Islander, Ulrika, 1975, et al.
(author)
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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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In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 13:3
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Journal article (peer-reviewed)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.
(author)
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Estrogens in rheumatoid arthritis; the immune system and bone
- 2011
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In: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 335:1, s. 14-29
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Research review (peer-reviewed)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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| 6. |
- Jochems, Caroline, 1973, et al.
(author)
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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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In: Clinical and Experimental Immunology. - Chichester : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 165:1, s. 121-129
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Journal article (peer-reviewed)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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| 7. |
- Jochems, Caroline, 1973, et al.
(author)
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Long-term anti-arthritic and anti-osteoporotic effects of raloxifene in established experimental postmenopausal polyarthritis.
- 2008
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In: Clinical and experimental immunology. - : Oxford University Press (OUP). - 1365-2249 .- 0009-9104. ; 152:3, s. 593-7
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Journal article (peer-reviewed)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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| 8. |
- Jochems, Caroline, 1973, et al.
(author)
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Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis.
- 2010
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In: BMC musculoskeletal disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 16:11
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Journal article (peer-reviewed)abstract
- 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.
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| 9. |
- Jochems, Caroline, 1973, et al.
(author)
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Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis
- 2007
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In: Arthritis Rheum. - : Wiley. - 0004-3591. ; 56:10, s. 3261-3270
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Journal article (peer-reviewed)abstract
- OBJECTIVE: In postmenopausal rheumatoid arthritis (RA), both estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. Hormone replacement therapy (HRT) with estradiol preserves bone mineral density (BMD) and ameliorates arthritis, but long-term therapy is no longer an option due to significant side effects. We therefore used a mouse model of human RA to test the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and osteoporosis. METHODS: Female DBA/1 mice were ovariectomized and arthritis was induced with collagen immunization. Mice received an injection of raloxifene, estradiol, or vehicle control, administered prophylactically or therapeutically, and thereafter the clinical arthritis score was evaluated continuously. At termination, BMD was analyzed with peripheral quantitative computed tomography. Paws were collected for histology, and sera were analyzed for cytokines and markers of bone and cartilage turnover. Levels of cytokine messenger RNA (mRNA) were investigated with real-time polymerase chain reaction. RESULTS: Treatment with raloxifene dramatically decreased the frequency and severity of arthritis. Effective preservation of bone and cartilage was seen in raloxifene-exposed mice, as demonstrated by increased BMD and decreased serum levels of cartilage oligomeric matrix protein in the raloxifene-treated mice compared with controls. Decreased levels of mRNA for both tumor necrosis factor alpha and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM. CONCLUSION: In a well-established model of postmenopausal 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. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.
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| 10. |
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| 11. |
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| 12. |
- Lundquist, Anna, et al.
(author)
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Interactions of drugs and an oligonucleotide with charged membranes analyzed by immobilized liposome chromatography
- 2006
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In: Biomedical Chromatography. - : Wiley. - 0269-3879 .- 1099-0801. ; 20, s. 83-87
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Journal article (peer-reviewed)abstract
- We studied the effect of charged lipids or detergent on the retention of drugs and an oligonucleotide by immobilized liposome chromatography to characterize solute-membrane interactions. This is a novel approach in analysis of oligonucleotide-liposome interactions. The charged lipids (phosphatidylserine or distearoyltrimethylammoniumpropane) or detergent (sodium dodecylsulfate) interacted electrostatically in a concentration-dependent matter with the solutes. The oligonucleotide ions presumably bound to the liposomes by multipoint interactions, which was saturable. Sodium dodecylsulfate seemed to affect the drug-membrane interactions more strongly than phosphatidylserine did, probably due to different positioning in the bilayer.
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| 13. |
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| 14. |
- Windahl, Sara H, 1971, et al.
(author)
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Identification of Target Cells for the Genomic Effects of Estrogens in Bone
- 2007
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 148:12, s. 5688-95
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Journal article (peer-reviewed)abstract
- Estrogen has bone protective effects, but the exact mechanism behind these effects remains unclear. The aim of the present study was to identify the primary target cells in bone for the classical genomic effects of estrogens in vivo. For this purpose we have used reporter mice with a luciferase gene under the control of three estrogen-responsive elements (EREs), enabling detection of in vivo activation of gene transcription. Three-month-old ovariectomized mice were treated with a single dose (50microg/kg) 17beta-estradiol (E2). Luciferase activity was analysed in several tissues and in different bone marrow-derived lymphocyte enriched/depleted preparations using MacsMouse CD19 (for B lymphocytes) or CD90 (for T lymphocytes) MicroBeads. Histological characterization of cells with high luciferase content was performed using immunohistochemistry. Both cortical bone and bone marrow displayed a rapid (within 1h) and pronounced E2-induced increase in luciferase activity. The luciferase activity in total bone marrow and in bone marrow depleted of lymphocytes was increased 6-8 times more than in either B lymphocyte and T lymphocyte enriched cell fractions 4h after the E2-injection, demonstrating that mature lymphocytes are not major direct targets for the genomic effect of estrogens in bone. Immunohistochemistry identified clear luciferase staining in hypertrophic growth plate chondrocytes, megakaryocytes, osteoblasts and lining cells, while no staining was seen in proliferative chondrocyte. Although most of the osteocytes did not display any detectable luciferase staining, a subpopulation of osteocytes both in cortical and trabecular bone stained positive for luciferase. In conclusion, hypertrophic growth plate chondrocytes, megakaryocytes, osteoblasts, lining cells and a subpopulation of osteocytes were identified to respond to estrogen via the classical ERE-mediated genomic pathway in bone. Furthermore, our findings indicate that possible direct estrogenic effects on the majority of osteocytes, not staining positive for luciferase, on proliferative chondrocytes and on mature lymphocytes are mediated by non-ERE actions.
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