ABSTRACT
Joint replacements have a longer durability in patients with high serum levels of adiponectin (APN) than in patients with low levels. We aimed to characterize the unknown pathophysiological effects of APN on wear particle-induced inflammation, apoptosis and osteolysis. Immunohistochemistry was performed to detect APN, its receptors and apoptosis in patients with and without aseptic loosening. Additionally, APN knockout mouse studies and pharmacological intervention of APN were performed in an established calvarial mouse model. Osteolysis and inflammation were quantified by histomorphometry and microcomputed tomography, apoptosis by immunohistochemistry and TUNEL assay. In a cell culture model, human monocyte-derived macrophages were incubated with or without metal wear debris particles and partially treated with APN. Expression of APN, AdipoR1 and calreticulin in specimens from patients with aseptic loosening were significantly higher than in patients without aseptic loosening. Administration of APN in mice significantly reduced wear particle-induced inflammation, osteolysis and the number of caspase-3-positive macrophages. The cell culture model showed that APN leads to significantly lower values of TNF-α. These findings support a prominent role of APN in the development of particle-induced osteolysis and APN may be therapeutically useful in patients with aseptic loosening.
Subject(s)
Adiponectin/metabolism , Arthroplasty, Replacement, Hip/adverse effects , Osteolysis/etiology , Osteolysis/metabolism , Prosthesis Failure/etiology , Adult , Aged , Aged, 80 and over , Animals , Apoptosis , Cells, Cultured , Disease Models, Animal , Female , Humans , In Situ Nick-End Labeling , Inflammation/pathology , Joint Capsule/metabolism , Joint Capsule/pathology , Macrophages/metabolism , Macrophages/pathology , Male , Mice, Inbred C57BL , Middle Aged , Models, Biological , Phagocytosis , Receptors, Adiponectin/metabolism , Skull/metabolism , Skull/pathologyABSTRACT
BACKGROUND AND AIMS: Liver and gut not only share alimentary but also immunological features. Major histocompatibility complex class I-related chains A and B (MIC A/B) function as indicators for cellular stress. These so called stress-induced ligands are suggested to play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) and are a prominent feature of celiac disease (CD). PATIENTS AND METHODS: In the present study, 24 patients with celiac disease and 20 patients with non-alcoholic steatohepatitis (NASH) were included. Liver enzymes, serum cell death markers (M30, M65), MIC B and expression of adiponectin were determined. RESULTS: Mean patient age was 42 years (18 - 69) for CD and 49 years (33 - 68) for the NASH group.âALT and AST values were lower in CD compared to NASH patients. While serum cell death markers were higher in NASH, the predominant type of cell death in CD was apoptosis. Also, expression of MIC B was significantly up-regulated in CD patients as compared to NASH patients. Adiponectin values were significantly lower in NASH compared to CD patients. CONCLUSION: Stress-induced ligands and apoptosis are induced in CD. Prospective studies need to determine the exact role of cellular stress and apoptosis in the gut-liver axis and the clinical implications to screen for NAFLD in CD patients.
Subject(s)
Adiponectin/immunology , Celiac Disease/immunology , Fatty Liver/immunology , Immunologic Factors/immunology , Oxidative Stress/immunology , Adolescent , Adult , Aged , Apoptosis/immunology , Female , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease , Young AdultABSTRACT
Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from hepatitis C virus (HCV)-negative vs HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human HSC line (LX2). Uptake of Huh7(Con1+) ABs by LX2 cells dose dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV(+) ABs exhibited a more pronounced effect than HCV(-) ABs. In contrast, neither noningested ABs nor nucleic acids obtained from Huh7, Huh7(Con1+) or HepG2 cells triggered those AB-dependent effects. Both the engulfment of Huh7(Con1+) ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation.
