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PI 3-kinase pathway is responsible for antiapoptotic effects of atrial natriuretic peptide in rat liver transplantation

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World Journal of Gastroenterology 2006年第7期12卷 1049-1055页

作者： Uwe Grutzner melanie keller Michael Bach Alexandra K Kiemer Herbert Meissner Manfred Bilzer Stefan Zahler Alexander L Gerbes Angelika M Vollmar Institute for Surgical Research Klinikum GroBhadernUniversity of MunichD-81377 MunichGermany Department of Pharmacy University of MunichD-81377 MunichGermany Department Institute of Pathology University of MunichD-81377 MunichGermany

AIM： To investigate the in vivo effect of atrial natriuretic peptide （ANP） and its signaling pathway during orthotopic rat liver transplantation.METHODS： Rats were infused with NaCI, ANP （5 μg/ kg）, wortmannin （WH, 16μg/kg）, or a combination of both for 20 min. Livers were stored in UW solution （4℃） for 24 h, transplanted and reperfused. Apoptosis was examined by caspase-3 activity and TUNEL staining. Phosphorylation of Akt and Bad was visualized by Western blotting and phospho-Akt-localization by confocal microscopy.RESULTS： ANP-pretreatment decreased caspase-3 activity and TUNELopositive cells after cold ischemia, indicating antiapoptotic effects of ANP in vivo. The an- tiapoptotic signaling of ANP was most likely caused by phosphorylation of Akt and Bad, since pretreatment with PI 3-kinase inhibitor WM abrogated the ANP-induced reduction of caspase-3 activity. Interestingly, analysis of liver tissue by confocal microscopy showed translocation of phosphorylated Akt to the plasma membrane of hepa- tocytes evoked by ANP.CONCLUSION： ANP activates the PI-3-kinase pathway in the liver in vivo leading to phosphorylation of Bad an event triggering antiapoptotic signaling cascade in ischemic liver.

关键词： Bad Apoptosis Hormonal preconditioning Ischemia reperfusion injury

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Hepatocyte cytoskeleton during ischemia and reperfusion -influence of ANP-mediated p38 MAPK activation

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World Journal of Gastroenterology 2005年第47期11卷 7418-7429页

作者： melanie keller Alexander L Gerbes Stefanie Kulhanek-Heinze Tobias Gerwig Uwe Grützner Nico van Rooijen Angelika M Vollmar Alexandra K Kiemer Department of Pharmacy Centre of Drug ResearchUniversity of MunichButenandtstr. 5-1381377 MunichGermany Department of Medicine Ⅱ Klinikum GroβhadernUniversity of MunichMarchionistr. 1781377 MunichGermany Angelika M Vollmar Alexandra K KiemerDepartment of PharmacyCentre of Drug ResearchUniversity of MunichButenandtstr. 5-1381377 MunichGermany Department of Pharmacy Centre of Drug ResearchUniversity of MunichButenandtstr. 5-1381377 MunichGermany Department of Medicine ⅡKlinikum GroβhadernUniversity of MunichMarchionistr. 1781377 MunichGermany Institute for Surgical Research Klinikum GroβhadernUniversity of MunichMarchionistr. 1781377 MunichGermany Vrije Universiteit VUMCDepartment of Molecular Cell BiologyFaculty of Medicine1081 BT AmsterdamThe Netherlands

AIM： To determine functional consequences of this activation, whereby we focused on a potential regulation of the hepatocyte cytoskeleton during ischernia and reperfusion. METHODS： For in vivo experiments, animals received ANP （5 μg/kg） intravenously. In a different experimental setting, isolated rat livers were perfused with KH-buffer ＋ANP （200 nmol/L）＋SB203580 （2 μmol/L）. Livers were then kept under ischernic conditions for 24 h, and either transplanted or reperfused. Actin, Hsp27, and phosphorylated Hsp27 were determined by Western blotting, p38 MAPK activity by in vitro phosphorylation assay. F-actin distribution was determined by confocal microscopy. RESULTS： We first confirmed that ANP preconditioning leads to an activation of p38 MAPK and observed alterations of the cytoskeleton in hepatocytes of ANP- preconditioned organs. ANP induced an increase of hepatic F-actin after ischemia, which could be prevented by the p38 MAPK inhibitor SB203580 but had no effect on bile flow. After ischemia untreated livers showed a translocation of Hsp27 towards the cytoskeleton and an increase in total Hsp27, whereas ANP preconditioning prohibited translocation but caused an augmentation of Hsp27 phosphorylation. This effect is also mediated via p38 MAPK, since it was abrogated by the p38 MAPK inhibitor SB203580. CONCLUSION： This study reveals that ANP-mediated p38 MAPK activation leads to changes in hepatocyte cytoskeleton involving an elevation of phosphorylated Hsp27 and thereby for the first time shows functional consequences of ANP-induced hepatic p38 MAPK activation.

关键词： Hormonal preconditioning Atrial natriuretic peptide Hsp 27 Actin Polymerization

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Procalcitonin is expressed in osteoblasts and limits bone resorption through inhibition of macrophage migration during intermittent PTH treatment

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Bone Research 2022年第1期10卷 107-121页

作者： Anke Baranowsky Denise Jahn Shan Jiang Timur Yorgan Peter Ludewig Jessika Appelt Kai K.Albrecht Ellen Otto Paul Knapstein Antonia Donat Jack Winneberger Lana Rosenthal Paul Köhli Cordula Erdmann melanie Fuchs Karl-Heinz Frosch Serafeim Tsitsilonis Michael Amling Thorsten Schinke Johannes keller Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-EppendorfHamburg 20246Germany Department of Osteology and Biomechanics University Medical Center Hamburg-EppendorfHamburg 20246Germany Center for Musculoskeletal Surgery Charité-Universitätsmedizin BerlinBerlin 13353Germany Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration Charité-Universitätsmedizin BerlinBerlin 13353Germany Department of Neurology University Medical Center Hamburg-EppendorfHamburg 20251Germany Berlin Institute of Health Berlin 10178Germany

Intermittent injections of parathyroid hormone(iPTH) are applied clinically to stimulate bone formation by osteoblasts, although continuous elevation of parathyroid hormone(PTH) primarily results in increased bone resorption. Here, we identified Calca,encoding the sepsis biomarker procalcitonin(ProCT), as a novel target gene of PTH in murine osteoblasts that inhibits osteoclast formation. During iPTH treatment, mice lacking ProCT develop increased bone resorption with excessive osteoclast formation in both the long bones and axial skeleton. Mechanistically, ProCT inhibits the expression of key mediators involved in the recruitment of macrophages, representing osteoclast precursors. Accordingly, ProCT arrests macrophage migration and causes inhibition of early but not late osteoclastogenesis. In conclusion, our results reveal a potential role of osteoblast-derived ProCT in the bone microenvironment that is required to limit bone resorption during iPTH.

关键词： treatment representing skeleton

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Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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Bone Research 2024年第1期12卷 199-214页

作者： Laura J.Brylka Assil-Ramin Alimy Miriam E.A.Tschaffon-Müller Shan Jiang Tobias Malte Ballhause Anke Baranowsky Simon von Kroge Julian Delsmann Eva Pawlus Kian Eghbalian Klaus Püschel Astrid Schoppa melanie Haffner-Luntzer David J.Beech Frank Timo Beil Michael Amling Johannes keller Anita Ignatius Timur A.Yorgan Tim Rolvien Thorsten Schinke Department of Osteology and Biomechanics University Medical Center Hamburg-Eppendorf20246 HamburgGermany Department of Trauma and Orthopedic Surgery University Medical Center Hamburg-Eppendorf20246 HamburgGermany Institute of Orthopedic Research and Biomechanics University Medical Center UlmBadenWürttemberg89081 UlmGermany Department Legal Medicine University Medical Center Hamburg-Eppendorf20246 HamburgGermany Leeds Institute of Cardiovascular and Metabolic Medicine School of MedicineUniversity of LeedsLS29JT LeedsUK

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell *** we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in *** we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)*** with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate ***,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth *** skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of ***,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage ***,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) *** further observed increased Piezo1 protein abundance in cartilaginous zones of human ***,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in ***,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

关键词： Piezo1 markedly ossification

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