RESUMO
Despite an increased understanding of the pathogenesis of osteoarthritis (OA) and the availability of a number of drugs designed to ameliorate its symptoms, a successful disease-modifying therapy remains elusive. Recent lines of evidence suggest that dehydroepiandrosterone (DHEA), a 19-carbon steroid hormone classified as an adrenal androgen, exerts a chondroprotective effect in OA patients, and it has been proven to be an effective DMOAD candidate that slows OA progression. However, the exact mechanisms underlying its anti-OA effect is largely unknown. This review summarizes emerging observations from studies of cell biology, preclinical animal studies, and preliminary clinical trials and describes the findings of investigations on this topic to develop an initial blueprint of the mechanisms by which DHEA slows OA progression. Presently, studies on DMOADs are increasing in importance but have met limited success. Encouragingly, the current data on DHEA are promising and may prove that DHEA-based treatment is efficacious for preventing and slowing human OA progression.
Assuntos
Cartilagem/metabolismo , Desidroepiandrosterona/farmacologia , Osteoartrite/tratamento farmacológico , Animais , Desidroepiandrosterona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica , HumanosRESUMO
OBJECTIVE: In this study, we investigated the effects of hinokitiol on matrix metalloproteinase (MMP)-1, -3, -13, collagen type II (Col2a1) and ß-catenin expressions in rat chondrocytes induced by interleukin-1ß and in an experimental rat model induced by intra-articular injection of mono-iodoacetate (MIA) into the knee. METHODS: Chondrocytes were cultured from the articular cartilage of 2-week-old rats. Passaged chondrocytes were pretreated with hinokitiol for 2h followed by co-incubation with IL-1ß for 24h. Quantitative real-time polymerase chain reaction and Western blotting were used to assess the expression of MMP-1, -3, -13, Col2a1 and ß-catenin. Chondrocytes were also treated with Licl, Dickkopf-1, and/or hinokitiol for 24h, the MMP-1, -3, -13 and ß-catenin protein levels determined by Western blotting. The in vivo effects of hinokitiol were assessed by morphological and histological analyses following MIA injection. RESULTS: Hinokitiol inhibited IL-1ß-stimulated MMP-1,-3 and -13 expressions and IL-1ß-induced activation of intracellular ß-catenin proteins in cultured chondrocytes. In vivo, morphological and histological examinations demonstrated that hinokitiol significantly ameliorated cartilage degeneration. CONCLUSIONS: Hinokitiol is an effective anti-inflammatory reagent that acts by inhibiting the Wnt/ß-catenin signaling pathway and could be a promising therapeutic agent for the prevention and treatment of osteoarthritis.
Assuntos
Anti-Inflamatórios/administração & dosagem , Condrócitos/efeitos dos fármacos , Cupressaceae/imunologia , Joelho/patologia , Monoterpenos/administração & dosagem , Osteoartrite/tratamento farmacológico , Fitoterapia , Tropolona/análogos & derivados , Animais , Células Cultivadas , Condrócitos/fisiologia , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Modelos Animais , Osteoartrite/imunologia , Ratos , Ratos Endogâmicos , Transdução de Sinais/efeitos dos fármacos , Tropolona/administração & dosagem , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
To investigate the in vivo effect of dehydroepiandrosterone (DHEA) on the expression of aggrecanases and their endogenous inhibitor in a rabbit model of OA. Ten New Zealand white rabbits underwent bilateral anterior cruciate ligament transection (ACLT). One knee of each rabbit was randomly assigned to receive 100 µM DHEA dissolved in dimethylsulphoxide (DMSO) and the other was treated with DMSO only. The treatment was given once a week for 5 weeks, starting 4 weeks after transection. All rabbits were euthanized 9 weeks after ACLT treatment, and the knee joints were evaluated by gene expression analysis. Intra-articular administration of DHEA significantly reduced the gene expression of aggrecanases, while markly increasing that of tissue inhibitor of metalloproteinase-3 (TIMP-3), an endogenous inhibitor of aggrecanases. DHEA may have beneficial effects on OA by influencing the balance between aggrecanases and TIMP-3 through which DHEA may protect against OA.
Assuntos
Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/enzimologia , Desidroepiandrosterona/farmacologia , Endopeptidases/metabolismo , Osteoartrite/enzimologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Ligamento Cruzado Anterior/cirurgia , Cartilagem Articular/patologia , Desidroepiandrosterona/uso terapêutico , Modelos Animais de Doenças , Endopeptidases/genética , Humanos , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Masculino , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Coelhos , Distribuição Aleatória , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismoRESUMO
Berberine shows anticancer, antibacterial, antiinflammatory and antioxidant effects and may be useful in many clinical applications. The effects of berberine on articular cartilage metabolism remain unknown, so this study was performed to evaluate these effects in vitro and in vivo. For the in vitro work, rat articular chondrocytes were cultured in a monolayer and matrix metalloproteinase-1 (MMP-1), -3, -13 and tissue inhibitor of metalloproteinase (TIMP-1) expression was evaluated by real-time quantitative PCR. Nitric oxide (NO) levels were determined using the Griess reaction, and glycosaminoglycan (GAG) release was measured using the dimethylmethylene blue method. For the in vivo work, berberine was administered by intraarticular injection, and the effects on MMPs and TIMP-1 were examined at the gene and protein levels. Berberine was found to inhibit the expression of MMP-1, -3 and -13, and increased the level of TIMP-1 at the mRNA level in a dose-dependent manner. In IL-1ß-induced rat articular chondrocytes, berberine decreased IL-1ß-induced GAG release and NO production. Meanwhile, high-dose berberine exhibited an anticatabolic effect in an IL-1ß-induced rat osteoarthritis (OA) model. These findings suggest that berberine may play a protective role in the development of OA and may be useful in the treatment of OA.
Assuntos
Berberina/farmacologia , Osteoartrite/tratamento farmacológico , Animais , Sequência de Bases , Cartilagem Articular/citologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Proliferação de Células/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Primers do DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/prevenção & controle , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Proteoglicanas/análise , RNA Mensageiro/análise , RNA Mensageiro/genética , RatosRESUMO
Diallyl sulphide (DAS) is known for its antioxidant, anticancer and detoxifying properties. The aim of this study was to investigate the effect of DAS on rabbit articular chondrocytes and cartilage in experimental osteoarthritis (OA) induced by anterior cruciate ligament transection (ACLT). DAS inhibited matrix metalloproteinase-1 (MMP-1), MMP-3 and MMP-13 expression in interleukin-1beta (IL-1ß)-induced chondrocytes. In an in vivo study, DAS ameliorated cartilage degradation as assessed by morphological and histological examination. Messenger RNA expression of MMP-1, MMP-3, MMP-13 and IL-1ß was inhibited by DAS in cartilage. In addition, DAS increased the collagen II level in cartilage. The results suggest that DAS may protect cartilage in the development of OA.