RESUMO
Both overuse and disuse of joints up-regulate matrix metalloproteinases (MMPs) in articular cartilage and cause tissue degradation; however, moderate (physiological) loading maintains cartilage integrity. Here, we test whether CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), a mechanosensitive transcriptional coregulator, mediates this chondroprotective effect of moderate mechanical loading. In vivo, hind-limb immobilization of Sprague-Dawley rats up-regulates MMP-1 and causes rapid, histologically detectable articular cartilage degradation. One hour of daily passive joint motion prevents these changes and up-regulates articular cartilage CITED2. In vitro, moderate (2.5 MPa, 1 Hz) intermittent hydrostatic pressure (IHP) treatment suppresses basal MMP-1 expression and up-regulates CITED2 in human chondrocytes, whereas high IHP (10 MPa) down-regulates CITED2 and increases MMP-1. Competitive binding and transcription assays demonstrate that CITED2 suppresses MMP-1 expression by competing with MMP transactivator, Ets-1 for its coactivator p300. Furthermore, CITED2 up-regulation in vitro requires the p38δ isoform, which is specifically phosphorylated by moderate IHP. Together, these studies identify a novel regulatory pathway involving CITED2 and p38δ, which may be critical for the maintenance of articular cartilage integrity under normal physical activity levels.
Assuntos
Cartilagem Articular/metabolismo , Articulações/fisiologia , Metaloproteinase 1 da Matriz/metabolismo , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Linhagem Celular , Condrócitos/metabolismo , Expressão Gênica , Humanos , Pressão Hidrostática , Imuno-Histoquímica , Masculino , Metaloproteinase 1 da Matriz/genética , Mutação , Ligação Proteica , Proteína Proto-Oncogênica c-ets-1/metabolismo , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Restrição Física , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Técnicas de Cultura de Tecidos , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Post-cystectomy recurrence of transitional-cell carcinoma (TCC) that is confined to the pelvis is uncommon, and few data exist to guide its management. we used weekly intra-arterial chemotherapy with gemcitabine and cisplatin in a consecutive series of 11 patients with this diagnosis. After 2 cycles of intra-arterial chemotherapy with gemcitabine (each cycle: 900 mg/m(2) on days 1, 8, and 15) plus cisplatin (each cycle: 30 mg/m(2) on days 1, 8, and 15), 3 patients achieved complete response (CR) and 8 patients partial response (PR). two pR patients achieved CR after surgery and radiotherapy for residual disease. Six pR patients died of disease progression 8 to 20 months after chemotherapy. Four CR patients have survived, free of disease, 17 to 43 months, and 1 CR patient died of a non-tumor-related cause 23 months after chemotherapy. Short course intra-arterial chemotherapy with a GC regimen thus appears to be highly effective in the subset of patients with recurrent TCC confined to the pelvis.