RESUMO
OBJECTIVE: Oncostatin M (OSM) is a member of the interleukin-6 cytokine family, with well-documented effects on cell growth and differentiation. OSM also has proinflammatory and cartilage degradative properties. The aim of this study was to investigate the significance of OSM in arthritis pathology using a neutralizing antibody in arthritis models. METHODS: Collagen-induced arthritis (CIA) was established in male DBA/1 mice. Reverse transcriptase-polymerase chain reaction was used to detect OSM messenger RNA (mRNA) message levels in arthritic joints. Neutralizing anti-OSM antibody or control immunoglobulin was administered on days 1 and 3 after disease onset. Animals were assessed for clinical arthritis for 2 weeks, followed by a histologic analysis of paws. Pristane-induced arthritis (PIA) was produced in male CBA mice dosed with anti-OSM or control immunoglobulin immediately before disease onset. Mice with PIA were assessed for clinical arthritis over a period of 100 days. RESULTS: Levels of mRNA for OSM, but not GAPDH, were elevated in arthritic joints of mice with CIA compared with those of normal controls. Mice with CIA treated with anti-OSM antibody showed significant amelioration of both the clinical severity (P < 0.01) and the number of affected paws (P < 0.01) compared with control animals. Histologic analysis confirmed these clinical findings, revealing a marked reduction in cellular infiltration of synovium and cartilage damage. In the PIA model, the incidence of arthritis was 65% in the control group compared with 0% in the anti-OSM-treated animals. CONCLUSION: These results demonstrate a key role for endogenously produced OSM as a potent mediator of joint pathology, and suggest that OSM might be a potentially important, novel therapeutic target for treatment of established rheumatoid arthritis.
Assuntos
Anticorpos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Proteínas de Bactérias , Peptídeos/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Chaperonina 60 , Chaperoninas/farmacologia , Colágeno/imunologia , Colágeno/farmacologia , Primers do DNA/química , Modelos Animais de Doenças , Edema/tratamento farmacológico , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Imunoglobulina G/administração & dosagem , Articulações/química , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Oncostatina M , Peptídeos/genética , Peptídeos/imunologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Terpenos/imunologia , Terpenos/farmacologiaRESUMO
Diclofenac in hyaluronan is analgesic and angiostatic. The depletion of substance P may be a common mechanism. Mice received diclofenac, diclofenac in hyaluronan, or saline i.v. for 5 days and snout substance P assessed: saline 2.80 +/- 0.23; 0.5 mg/kg diclofenac 2.03 +/- 0.20 (P < 0.05); diclofenac in hyaluronan 1.88 +/- 0.21 (P < 0.02); capsaicin 1.45 +/- 0.26 fmol/mg tissue (P < 0.005). Substance P recovered by 5 days (diclofenac in hyaluronan, capsaicin) and 24 h (diclofenac). Diclofenac may deplete substance P in analgesia, and hyaluronan prolong the depletion.
Assuntos
Analgésicos/farmacologia , Diclofenaco/farmacologia , Substância P/metabolismo , Analgésicos/administração & dosagem , Animais , Diclofenaco/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Ácido Hialurônico/administração & dosagem , CamundongosRESUMO
Topical diclofenac in 2.5% hyaluronan inhibits basal cell carcinoma, actinic keratosis, and murine colon-26 growth in vivo. colon-26 tumor growth was preceded by angiogenesis and reduced apoptotic and mitotic indices. Diclofenac reduced proliferation and viability in vitro, and stimulated apoptosis. Hyaluronan inhibited proliferation and viability at 1 mg/ml but was inactive below this level. Topical application of diclofenac inhibited tumor prostaglandin synthesis and retarded angiogenesis and tumor growth (ratio of treatment:control, 0.174). The mitotic index remained unaltered in vivo, whereas the apoptotic index and necrosis were increased. Topical vehicle exhibited slight antitumor and antiangiogenesis activity. The substantial quantities of diclofenac delivered locally in hyaluronan may exhibit antitumor activity in similar fashion to those seen in vitro and explain its clinical efficacy.
