Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice.
Oncostatin M (OSM) is a member of the IL-6 family of cytokines. Mice deficient in the OSM receptor (OSMR(-/-)) showed impaired liver regeneration with persistent parenchymal necrosis after carbon tetrachloride (CCl(4)) exposure. The recovery of liver mass from partial hepatectomy was also significantly delayed in OSMR(-/-) mice. In contrast to wildtype mice, CCl(4) administration only marginally induced expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 genes in OSMR(-/-) mice, correlating with the increased gelatinase activity of matrix metalloproteinase (MMP)-9 and matrix degradation in injured livers. The activation of STAT3 and expression of immediate early genes and cyclins were decreased in OSMR(-/-) liver, indicating that OSM signaling is required for hepatocyte proliferation and tissue remodeling during liver regeneration. We also found that CCl(4) administration in IL-6(-/-) mice failed to induce OSM expression and that OSM administration in IL-6(-/-) mice after CCl(4) injection induced the expression of cyclin D1 and proliferating cell nuclear antigen, suggesting that OSM is a key mediator of IL-6 in liver regeneration. Consistent with these results, administration of OSM ameliorated liver injury in wildtype mice by preventing hepatocyte apoptosis as well as tissue destruction. In conclusion, OSM and its signaling pathway may provide a useful therapeutic target for liver regeneration.
Stem Cell Regulation Project, Kanagawa Academy of Science and Technology (KAST), Kawasaki, Kanagawa, Japan.
Koji
K
Nakamura
Hidenori
H
Nonaka
Hiroki
H
Saito
Minoru
M
Tanaka
Atsushi
A
Miyajima
D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism; D018121:Receptors, Cytokine / Q000172:deficiency*; D053677:Receptors, Oncostatin M; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D015850:Interleukin-6; C508352:Osm protein, mouse; D010455:Peptides; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D019715:Tissue Inhibitor of Metalloproteinase-1; D053683:Oncostatin M; D019716:Tissue Inhibitor of Metalloproteinase-2; D002251:Carbon Tetrachloride; D020780:Matrix Metalloproteinase 9