Protease profiling of liver fibrosis reveals the adam metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of TGF-β

International audienceDuring chronic liver disease, tissue remodeling leads to dramatic changes and accumulation of matrix components. Matrix metalloproteases and their inhibitors have been involved in the regulation of matrix degradation. However, the role of other proteases remains incompletely defined. We undertook a gene expression screen of human liver fibrosis samples using a dedicated gene array selected for relevance to protease activities, identifying the ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif, 1) gene as an important node of the protease network. Upregulation of ADAMTS1 in fibrosis was found to be associated with hepatic stellate cell (HSC) activation. ADAMTS1 is synthesized as 110-kDa latent forms and processed by HSCs to accumulate as 87-kDa mature forms in fibrotic tissues. Structural evidence suggested that the thrombospondin motif-containing domain from ADAMTS1 may be involved in interactions with, and activation of, the major fibrogenic cytokine, TGF-β. Indeed, we observed direct interactions between ADAMTS1 and latency-associated peptide-TGF-β (LAP-TGF-β). ADAMTS1 induces TGF-β activation through the interaction of the ADAMTS1 KTFR peptide with the LAP-TGF-β LKSL peptide. Down-regulation of ADAMTS1 in HSCs decreases the release of TGF-β competent for transcriptional activation and KTFR competitor peptides directed against ADAMTS1 block HSC-mediated release of active TGF-β. Using a mouse liver fibrosis model, we show that CCl(4) treatment induces ADAMTS1 expression in parallel to that of type I collagen. Importantly, concurrent injection of the KTFR peptide prevents liver damage. CONCLUSION: Our results indicate that up-regulation of ADAMTS1 in HSCs constitutes a new mechanism for control of TGF-β activation in chronic liver disease. (HEPATOLOGY 2011.)

Sodium nitroprusside-induced osteoblast apoptosis is mediated by long chain ceramide and is decreased by raloxifene.

Release of high levels of nitric oxide (NO) is associated with osteoblastic cell death. The mechanisms of NO-induced cytotoxicity are not well documented and it is presently not known if estrogenic compounds prevent this effect. We studied the role of ceramides in cell death induced by the NO donor sodium nitroprusside (SNP) and we tested the possibility that 17beta-estradiol, the anti-estrogen ICI 182.780 and two selective estrogen receptor modulators raloxifene and tamoxifen modify osteoblastic cell apoptosis. SNP dose-dependently decreased MC3T3-E1 osteoblast viability, increased NO production in the culture media and enhanced the release of intracellular ceramides C22 and C24. Cell death induced by SNP was partially inhibited when MC3T3-E1 cells were pretreated with raloxifene and tamoxifen but was not modified when the cells were pretreated with 17beta-estradiol or ICI 182.780. Cell death induced by SNP resulted from apoptosis as demonstrated by Annexin-V and propidium iodide labeling and a reduction of SNP-induced MC3T3-E1 apoptosis was confirmed in the presence of raloxifene and tamoxifen. SNP induction of C22 and C24 production was inhibited by a pretreatment with raloxifene but not with 17beta-estradiol. Moreover, the synthetic ceramide C24 (0.75 and 1microM) decreased MC3T3-E1 cell viability and osteoblast cell death induced by C24 was partially decreased by raloxifene and to a lesser extent by 17beta-estradiol. These data demonstrate that SNP-induced cell death is mediated by the long chain ceramides C22 and C24 and that raloxifene protected osteoblast from apoptosis induced by SNP, an effect that might be relevant to its pharmacological properties on bone remodeling

Écriture et silence au xxe siècle

L’un des signes distinctifs du xxe siècle est l’émancipation du silence dans l’écriture, le désir de comprendre l’écriture hors de la domination du logos. Il y va d’une métamorphose du silence dans l’écriture du xxe siècle et d’une métamorphose de l’écriture du xxe siècle par la densité nouvelle du silence. L’enjeu est celui d’une critique de l’écriture par le silence en vue d’une façon neuve de penser l’écriture. Cette recherche engage une tentative de définition de l’écriture au xxe siècle en termes de tension entre le mot et le silence. Les questions soumises au travail collectif sont nombreuses : quelle est l’origine (onto logique, métaphysique, historique) de l’ascendant du silence dans l’écriture du xxe siècle ? Quelle est la nature et la fonction de ce silence ? Pourquoi le silence tend-il à être, au xxe siècle, une limite à laquelle l’écrire ne cesse de se heurter et de se mesurer ? En quoi la question du silence pose-t-elle celle de la légitimité de l’écriture au xxe siècle ? Comment le silence s’incarne-t-il dans la matière verbale ? Une architecture bâtie en fonction des genres littéraires a paru la plus apte à mettre en relief la remarquable polysémie du silence inentendue jusque-là : est tour à tour étudié l’échange de substance entre roman et silence, théâtre et silence, poésie et silence. L’élargissement de la réflexion à la musique et à la danse s’impose de lui-même tant le silence acquiert au xxe siècle une valeur et une fécondité musicales et chorégraphiques fondamentales. S’impose aussi l’élargissement de la recherche au cinéma qui est indissociable d’une exploration des possibles du silence

La cartographie des sols à moyennes échelles en France métropolitaine.

National audienc