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1.
Arthritis Res Ther ; 13(3): R96, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21689408

RESUMO

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 µg/d), estradiol (E2) (1 µg/d) or raloxifene (Ral) (120 µg/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.


Assuntos
Artrite Experimental/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Dexametasona/farmacologia , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Cloridrato de Raloxifeno/farmacologia , Animais , Artrite Experimental/complicações , Artrite Experimental/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Quimioterapia Combinada , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Glucocorticoides/farmacologia , Articulações/efeitos dos fármacos , Articulações/patologia , Camundongos , Camundongos Endogâmicos DBA , Osteoporose/complicações , Ovariectomia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
2.
BMC Musculoskelet Disord ; 11: 284, 2010 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-21159208

RESUMO

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.


Assuntos
Artrite Experimental/prevenção & controle , Estradiol/uso terapêutico , Estrogênios/fisiologia , Mutação/genética , NADPH Oxidases/fisiologia , Osteoartrite/prevenção & controle , Cloridrato de Raloxifeno/uso terapêutico , Animais , Artrite Experimental/epidemiologia , Artrite Experimental/fisiopatologia , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Estradiol/farmacologia , Feminino , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Camundongos Mutantes , NADPH Oxidases/genética , Osteoartrite/epidemiologia , Osteoartrite/fisiopatologia , Ovariectomia , Prevalência , Cloridrato de Raloxifeno/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
3.
Arthritis Rheum ; 62(2): 524-33, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20112355

RESUMO

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.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Anticorpos/sangue , Artrite Experimental/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Interleucina-6/sangue , Articulações/patologia , Linfopoese/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos DBA , Tamanho do Órgão , Osteoporose/tratamento farmacológico , Osteoporose/imunologia , Osteoporose/metabolismo , Ovariectomia , Receptores de Estrogênio , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Útero/anatomia & histologia , Útero/efeitos dos fármacos
4.
Arthritis Rheum ; 56(10): 3261-70, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17907171

RESUMO

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.


Assuntos
Artrite Experimental/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Pirrolidinas/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tiofenos/farmacologia , Animais , Artrite/tratamento farmacológico , Artrite Experimental/sangue , Citocinas/sangue , Feminino , Humanos , Camundongos , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Ligante RANK/metabolismo , RNA Mensageiro/análise , Cloridrato de Raloxifeno/análogos & derivados , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
5.
Arthritis Res Ther ; 7(4): R837-43, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15987485

RESUMO

Generalized osteoporosis in postmenopausal rheumatoid arthritis (RA) is caused both by estrogen deficiency and by the inflammatory disease. The relative importance of each of these factors is unknown. The aim of this study was to establish a murine model of osteoporosis in postmenopausal RA, and to evaluate the relative importance and mechanisms of menopause and arthritis-related osteoporosis. To mimic postmenopausal RA, DBA/1 mice were ovariectomized, followed by the induction of type II collagen-induced arthritis. After the mice had been killed, paws were collected for histology, one femur for bone mineral density (BMD) and sera for analyses of markers of bone resorption (RatLaps; type I collagen cross-links, bone formation (osteocalcin) and cartilage destruction (cartilage oligomeric matrix protein), and for the evaluation of antigen-specific and innate immune responsiveness. Ovariectomized mice displayed more severe arthritis than sham-operated controls. At termination of the experiment, arthritic control mice and non-arthritic ovariectomized mice displayed trabecular bone losses of 26% and 22%, respectively. Ovariectomized mice with arthritis had as much as 58% decrease in trabecular BMD. Interestingly, cortical BMD was decreased by arthritis but was not affected by hormonal status. In addition, markers of bone resorption and cartilage destruction were increased in arthritic mice, whereas markers of bone formation were increased in ovariectomized mice. This study demonstrates that the loss of endogenous estrogen and inflammation contribute additively and equally to osteoporosis in experimental postmenopausal polyarthritis. Markers of bone remodeling and bone marrow lymphocyte phenotypes indicate different mechanisms for the development of osteoporosis caused by ovariectomy and arthritis in this model.


Assuntos
Artrite Experimental/sangue , Estrogênios/deficiência , Osteoporose/sangue , Animais , Artrite/sangue , Artrite/patologia , Artrite Experimental/patologia , Densidade Óssea/fisiologia , Galinhas , Feminino , Inflamação/sangue , Inflamação/patologia , Camundongos , Camundongos Endogâmicos DBA , Osteogênese/fisiologia , Osteoporose/patologia , Ovariectomia
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