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1.
Endocrinology ; 157(3): 1013-20, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26745543

RESUMO

In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17ß-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.


Assuntos
Artrite Experimental/diagnóstico por imagem , Artrite Reumatoide/diagnóstico por imagem , Autoanticorpos/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/diagnóstico por imagem , Citocinas/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Indóis/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Doenças Ósseas Metabólicas/imunologia , Citocinas/imunologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Imunoglobulina G/efeitos dos fármacos , Imunoglobulina G/imunologia , Interleucina-6/imunologia , Camundongos , Ovariectomia , Radiografia , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos
2.
Endocrinology ; 155(3): 889-96, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24424045

RESUMO

Dehydroepiandrosterone (DHEA) is an abundant steroid hormone, and its mechanism of action is yet to be determined. The aim of this study was to elucidate the importance of androgen receptors (ARs) and estrogen receptors (ERs) for DHEA function. Orchidectomized C57BL/6 mice were treated with DHEA, DHT, 17ß-estradiol-3-benzoate (E2), or vehicle. Orchidectomized AR-deficient (ARKO) mice and wild-type (WT) littermates were treated with DHEA or vehicle for 2.5 weeks. At termination, bone mineral density (BMD) was evaluated, thymus and seminal vesicles were weighted, and submandibular glands (SMGs) were histologically examined. To evaluate the in vivo ER activation of the classical estrogen signaling pathway, estrogen response element reporter mice were treated with DHEA, DHT, E2, or vehicle, and a reporter gene was investigated in different sex steroid-sensitive organs after 24 hours. DHEA treatment increased trabecular BMD and thymic atrophy in both WT and ARKO mice. In WT mice, DHEA induced enlargement of glands in the SMGs, whereas this effect was absent in ARKO mice. Furthermore, DHEA was able to induce activation of classical estrogen signaling in bone, thymus, and seminal vesicles but not in the SMGs. In summary, the DHEA effects on trabecular BMD and thymus do not require signaling via AR and DHEA can activate the classical estrogen signaling in these organs. In contrast, DHEA induction of gland size in the SMGs is dependent on AR and does not involve classical estrogen signaling. Thus, both ERs and ARs are involved in mediating the effects of DHEA in an organ-dependent manner.


Assuntos
Desidroepiandrosterona/fisiologia , Regulação da Expressão Gênica , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Adjuvantes Imunológicos/química , Androgênios/metabolismo , Animais , Densidade Óssea , Osso e Ossos/metabolismo , Desidroepiandrosterona/farmacologia , Di-Hidrotestosterona/metabolismo , Estrogênios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Glândulas Seminais/metabolismo , Glândula Submandibular/metabolismo , Timo/metabolismo
3.
Arthritis Rheum ; 65(11): 2857-65, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23918694

RESUMO

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.


Assuntos
Antígenos/farmacologia , Artrite Experimental/patologia , Osteoartrite do Joelho/patologia , Osteoporose/patologia , Sinovite/patologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Densidade Óssea/imunologia , Modelos Animais de Doenças , Feminino , Fêmur/metabolismo , Fêmur/patologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Monócitos/metabolismo , Monócitos/patologia , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patologia , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/farmacologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Sinovite/induzido quimicamente , Sinovite/metabolismo
4.
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
5.
Clin Immunol ; 140(1): 37-46, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21459677

RESUMO

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.


Assuntos
Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Estradiol/análogos & derivados , Osteoporose Pós-Menopausa/prevenção & controle , 2-Metoxiestradiol , Animais , Modelos Animais de Doenças , Estradiol/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos DBA , Ovariectomia
6.
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
7.
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
8.
Rheumatology (Oxford) ; 48(7): 785-90, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19416946

RESUMO

OBJECTIVE: The aim of the study was to prospectively investigate the effects of HRT on serum soluble receptor for advanced glycation end product (sRAGE) levels in RA patients and to determine whether sRAGE production is related to bone/cartilage metabolism. METHODS: Eighty-eight post-menopausal RA patients were randomized to receive vitamin D3 and calcium supplementation with or without HRT (oestradiol plus noretisterone acetate). The levels of total sRAGE in sera were measured before, 1 and 2 years after treatment initiation. Potential associations between sRAGE levels, bone/cartilage metabolic markers and BMD were investigated. RESULTS: Patients receiving HRT displayed significantly decreased levels of serum sRAGE at 1 and 2 years as compared with levels at study entry. The increase in serum oestradiol was associated with the decline in sRAGE levels. Importantly, sRAGE levels at baseline significantly correlated with bone/cartilage turnover markers including C-terminal propeptide of type I procollagen, carboxyterminal telopeptide of type I collagen and cartilage oligomeric matrix protein, and the decrease of sRAGE levels paralleled with diminished concentration of these molecules. BMD in hip and femoral neck and progression of Larsen score at 1 year were associated with baseline sRAGE levels. The decline in sRAGE levels significantly correlated with an increase in total BMD following 2 years of treatment in patients receiving HRT but not in the control group. CONCLUSION: Our findings suggest that HRT decreases the levels of endogenous sRAGE in post-menopausal RA patients implicating its role in sRAGE regulation. In addition, serum sRAGE was associated with BMD and markers of bone/cartilage metabolism. These data suggest that sRAGE is involved directly or indirectly in bone metabolism. Trial registration. Current Controlled Trials, ISRCTN46523456, http://www.controlled-trials.com/isrctn/search.html?srch=ISRCTN46523456.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Terapia de Reposição de Estrogênios , Pós-Menopausa/metabolismo , Receptores Imunológicos/sangue , Fosfatase Alcalina/sangue , Artrite Reumatoide/metabolismo , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea , Osso e Ossos/metabolismo , Cálcio/administração & dosagem , Cartilagem/metabolismo , Proteína de Matriz Oligomérica de Cartilagem , Colecalciferol/administração & dosagem , Estradiol/administração & dosagem , Proteínas da Matriz Extracelular/sangue , Feminino , Glicoproteínas/sangue , Humanos , Proteínas Matrilinas , Pessoa de Meia-Idade , Noretindrona/administração & dosagem , Noretindrona/análogos & derivados , Acetato de Noretindrona , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Receptor para Produtos Finais de Glicação Avançada , Estatísticas não Paramétricas
9.
J Clin Endocrinol Metab ; 94(6): 2044-51, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19318446

RESUMO

CONTEXT: Serum levels of the sex steroid prohormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) decline upon aging and are reduced in primary Sjogren's syndrome. OBJECTIVE: Our aim was to investigate: 1) effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites; 2) relationships between steroid levels and disease characteristics; and 3) whether these parameters were influenced by DHEA. DESIGN: Twenty-three postmenopausal women with primary Sjogren's syndrome and subnormal levels of DHEA-S were included in a randomized, 9-month, controlled, double blind crossover study. Liquid chromatography/mass spectrometry (MS)/MS and gas chromatography/MS were used to measure the sex steroids. Anti-SS-A/Ro and/or anti-SS-B/La, salivary gland focus score, salivary flow rates, dry mouth and eye symptoms, and routine laboratory tests were assessed. RESULTS: Baseline erythrocyte sedimentation rate was inversely correlated with testosterone (Testo), dihydrotestosterone, and DHEA-S (rs = -0.42, -0.45, and -0.58, respectively). Dry mouth symptoms correlated with low Testo and androstenedione, whereas dry eyes correlated with low estrogens, most strongly estrone (rs = -0.63). Presence of anti-SS-A and/or anti-SS-B was independently associated with low estradiol (area under the receiver operating characteristic curve, 0.82). All metabolites increased during DHEA but not during placebo. The relative increases were less for estrogens and Testo compared to dihydrotestosterone and glucuronidated androgen metabolites. Dry mouth symptoms decreased during DHEA therapy. CONCLUSIONS: Disease manifestations in primary Sjogren's syndrome were associated with low sex hormone levels, dry mouth symptoms with low androgens, and dry eyes with low estrogens. Exogenous DHEA was preferentially transformed into androgens rather than into estrogens.


Assuntos
Desidroepiandrosterona/uso terapêutico , Hormônios Esteroides Gonadais/sangue , Síndrome de Sjogren/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Concentração Osmolar , Placebos , Síndrome de Sjogren/sangue , Síndrome de Sjogren/diagnóstico , Adulto Jovem
10.
J Rheumatol ; 35(10): 2005-11, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18709689

RESUMO

OBJECTIVE: To assess the role of resistin in primary Sjögren's syndrome (pSS) and its relation to local inflammation. METHODS: Blood and saliva were collected from 37 patients with pSS (duration of symptoms 12.6+/-1 yrs) and 32 healthy controls. Expression of resistin in salivary glands was visualized immunohistologically, and levels of resistin were detected by ELISA. Levels of resistin were evaluated at baseline and following oral dehydroepiandrosterone (DHEA) treatment (50 mg/day). The effect of DHEA treatment on the secretion of resistin was assessed in vitro in human leukocytes after challenge with insulin and lipopolysaccharide. RESULTS: Levels of resistin in saliva were significantly higher in patients with pSS than in controls, while circulating levels of resistin were similar in both groups. Resistin was expressed in the epithelial cells of striated ducts and in the lymphocytic foci. Resistin levels in saliva were related to the intensity of inflammation in the minor salivary glands of pSS patients. No changes of the levels of resistin in blood or saliva were observed during DHEA treatment. Exposure of naive leukocytes to DHEA in vitro induced significant expression of resistin compared to nonstimulated peripheral blood mononuclear cells (p=0.031). CONCLUSION: We showed that levels of resistin are upregulated locally in the salivary glands of patients with pSS; and that the levels of resistin correspond to the intensity of lymphocytic inflammation in patients with pSS. We suggest that resistin is expressed in the salivary glands of patients with pSS and may be a driving factor of local inflammation.


Assuntos
Resistina/metabolismo , Saliva/química , Glândulas Salivares Menores/metabolismo , Síndrome de Sjogren/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Adulto , Idoso , Biomarcadores , Estudos de Casos e Controles , Desidroepiandrosterona/uso terapêutico , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Glândulas Salivares Menores/imunologia , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia , Regulação para Cima
11.
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
12.
J Orthop Res ; 25(3): 304-10, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17089391

RESUMO

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.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Artrite Experimental/tratamento farmacológico , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/sangue , Difosfonatos/farmacologia , Quimioterapia Combinada , Feminino , Imidazóis/farmacologia , Interleucina-6/sangue , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoporose/prevenção & controle , Staphylococcus aureus , Ácido Zoledrônico
13.
Proc Natl Acad Sci U S A ; 104(1): 258-63, 2007 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-17185416

RESUMO

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-kappaB 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.


Assuntos
Artrite Experimental/prevenção & controle , Etanol/farmacologia , Animais , Artrite Experimental/imunologia , Densidade Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Colágeno Tipo II/imunologia , Imunidade Inata/efeitos dos fármacos , Interleucina-10/sangue , Interleucina-6/sangue , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , NF-kappa B/fisiologia , Testosterona/biossíntese , Fator de Transcrição AP-1/fisiologia
14.
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
15.
J Rheumatol ; 30(7): 1456-63, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12858441

RESUMO

OBJECTIVE: Hormone replacement therapy (HRT) is known to exert a positive effect in preventing bone loss and a beneficial effect on the disease activity in rheumatoid arthritis (RA). We evaluated the effects of HRT on bone mineral density (BMD) and on the course of established RA. METHODS: Eighty-eight postmenopausal women with RA were randomly allocated to receive HRT, vitamin D3, and calcium supplementation or vitamin D3 and calcium supplementation alone for 2 years. The effects of additional HRT on laboratory and clinical measures of disease activity, quality of life, and BMD and on radiographic joint damage were investigated. RESULTS: Treatment with HRT suppressed signs of inflammation as shown by reduction in erythrocyte sedimentation rate (ESR) (p = 0.025) and an elevation in hemoglobin concentration (p = 0.007), a better clinical outcome assessed by response on the Disease Activity Score 28 (DAS28) (p = 0.036), increased BMD in the forearm, proximal femur and spine (p < 0.01), and retarded (p = 0.026) progression of joint destruction among patients with radiological progressive disease. No significant effect on quality of life was seen. CONCLUSION: Two years of HRT in women with active RA had significant ameliorating effects on inflammation, DAS28 response, and BMD and was associated with slower progression of radiological joint destruction. The mechanisms by which HRT exerts its effects remain to be elucidated. We suggest HRT can be used in addition to conventional therapy in the management of postmenopausal patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Absorciometria de Fóton , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Sedimentação Sanguínea , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Progressão da Doença , Feminino , Nível de Saúde , Humanos , Articulações/efeitos dos fármacos , Articulações/fisiopatologia , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Método Simples-Cego , Inquéritos e Questionários
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