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Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

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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A new perspective is needed for positive selection of germinal center B cells with higher-affinity B cell receptors

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Cellular & Molecular Immunology 2022年第2期19卷 145-146页

作者： timo Gaber frank Buttgereit Department of Rheumatology and Clinical Immunology Charité-Universitätsmedizin Berlincorporate member of Freie Universität Berlin and Humboldt Universität zu BerlinBerlinGermany.

In a recent issue of Nature Immunology,Chen et *** differential expression signatures of metabolic programs within the germinal center(GC)compartment to distinguish GC B cells from different zones[1].Furthermore,they identified an important role of oxidative phosphorylation(OXPHOS)in the process of positive selection of B cells with higher-affinity B cell receptors(BCRs)in *** are inducible secondary lymphoid microanatomical structures that provide niches for B cells to capture and present antigens in the light zone(LZ)and to undergo clonal expansion and BCR somatic hypermutation(SHM)in the dark zone(DZ)*** migration of activated GC B cells between the LZ and DZ is assumed to result in positive selection of clones with higher-affinity B cell antigen *** clones are characterized by accelerated cell division,suggesting a genomic program activated by BCR and CD40 signaling[2].

关键词： center positive signature

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New insights into the fascinating world of glucocorticoids:the dexamethasone-miR-342-Rictor axis in regulatory T cells

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Cellular & Molecular Immunology 2021年第3期18卷 520-522页

作者： frank Buttgereit timo Gaber Department of Rheumatology and Clinical Immunology Charity University MedicineBerlinGermany

In a recent issue of Immunity,Kim et *** previously unknown effects of glucocorticoids on murine regulatory T(Treg)cells,and this report added another very interesting perspective to the already very diverse body of knowledge about these important hormones and therapeutics compared to the body of knowledge about other clinically used drugs.1 Treg cells are important regulators of the immune response in autoimmune and allergic inflammation.

关键词： drugs allergic

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Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF–RANKL signaling

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Bone Research 2018年第1期6卷 50-59页

作者： Alexander Bartelt Friederike Behler-Janbeck F.timo beil Till Koehne Brigitte Müller Tobias Schmidt Markus Heine Laura Ochs Tayfun Yilmaz Martin Dietrich Jan P.Tuckermann Michael Amling Joachim Herz Thorsten Schinke Joerg Heeren Andreas Niemeier Department of Orthopaedics University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Biochemistry and Molecular Cell Biology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Osteology and Biomechanics University Medical Center Hamburg-EppendorfMartinistr5220246 HamburgGermany Department of Orthodontics University Medical Center Hamburg-EppendorfMartinistr52 20246 HamburgGermany Department of Anatomy and Experimental Morphology University Medical Center Hamburg-EppendorfMartinistr.5220246 HamburgGermany Department of Molecular Genetics University of Texas Southwestern Medical CenterDallasTX 75390USA Institute for Comparative Molecular Endocrinology University of UlmUlmGermany Correspondence:Andreas Niemeier Department of Genetics and Complex Diseases&Sabriülker Center Harvard T.H.Chan School of Public Health665 Huntington AvenueBostonMA 02115USA

Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1(Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone *** lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand(RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor(PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF–RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans.

关键词： PDGFRβ RANKL activator receptor imatinib axis gene vivo

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Optimal Placing of Wind Turbines: Modelling the Uncertainty

Optimal Placing of Wind Turbines: Modelling the Uncertainty

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作者： timo Leenman frank Phillipson TNO Delftthe Netherlands

When looking at the optimal place to locate a wind turbine, trade-offs have to be made between local placement and spreading: transmission loss favours local placements and the correlation between the stochastic productions of wind turbines favours spreading. In this paper steps are described to determine the locations of new wind mills that minimize energy loss on the High Voltage power grid. A vindication of the used power grid model is provided, the simulation procedure for stochastic wind power is described and the required mathematical optimization models are described as well as implemented. Results are shown and their relation to real life problems is discussed. The analysis leads to the observation that in reality the entire Dutch coast is popular to locate wind turbines but the only region where this leads to actual reduction of the losses is the North(Groningen and Friesland). Next to this, at the current share of wind energy in the total network load, a spreading strategy to reduce variance of total wind power production does not seem advisable. At higher penetration(30%or more) spreading will become important.

关键词： Optimizing energy generation wind turbines placement transportation losses optimization methods

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Human immune cells＇ behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model

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Cellular & Molecular Immunology 2013年第2期10卷 151-158页

作者： Paula Hoff Patrick Maschmeyer timo Gaber Tabea Schiitze Tobias Raue Katharina Schmidt-Bleek Rene Dziurla Saskia Schellmann Ferenz Leonard Lohanatha Eric Rohner Andrea Ode Gerd-Riidiger Burmester Georg N Duda Carsten Perka frank Buttgereit Department of Rheumatelogy and Clinical Immunology Charite University Hospital Berlin Germany German Arthritis Research Center (DRFZ) Berlin Germany Berlin-Brandenburg Center for Regenerative Therapies (BCRT) Berlin Germany Julius Wolff Institute Berlin Germany Department of Orthopedics Charite University Hospital Berlin Germany These authors contributed equally to this work

The initial inflammatory phase of bone fracture healing represents a critical step for the outcome of the healing process. However, both the mechanisms initiating this inflammatory phase and the function of immune cells present at the fracture site are poorly understood. In order to study the early events within a fracture hematoma, we established an in vitro fracture hematoma model： we cultured hematomas forming during an osteotomy （artificial bone fracture） of the femur during total hip arthroplasty （THA） in vitro under bioenergetically controlled conditions. This model allowed us to monitor immune cell populations, cell survival and cytokine expression during the early phase following a fracture. Moreover, this model enabled us to change the bioenergetical conditions in order to mimic the in vivo situation, which is assumed to be characterized by hypoxia and restricted amounts of nutrients. Using this model, we found that immune cells adapt to hypoxia via the expression of angiogenic factors, chemoattractants and pro-inflammatory molecules. In addition, combined restriction of oxygen and nutrient supply enhanced the selective survival of lymphocytes in comparison with that of myeloid derived cells （i.e., neutrophils）. Of note, non-restricted bioenergetical conditions did not show any similar effects regarding cytokine expression and/or different survival rates of immune cell subsets. In conclusion, we found that the bioenergetical conditions are among the crucial factors inducing the initial inflammatory phase of fracture healing and are thus a critical step for influencing survival and function of immune cells in the early fracture hematoma.

关键词： apoptosis fracture hematoma model hypoxia immune cells inflammation

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Innovative immunohistochemistry identifies MMP-9 expressing macrophages at the invasive front of murine HCC

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World Journal of Hepatology 2010年第5期2卷 175-179页

作者： Martin Roderfeld timo Rath frank Lammert Christian Dierkes Jürgen Graf Elke Roeb Justus-Liebig-University Giessen Department of Medicine ⅡGastroenterologyGiessen 35385Germany Department of Internal Medicine Ⅱ Saarland University HospitalSaarland University Justus-Liebig-University Giessen Department of Pathology Philipps-University Marburg Department of Anaesthesiology and Intensive Care35033 Marburg and Pas-senger Medical CareDeutsche Lufthansa AGFrankfurt 60546Germany

AIM:To investigate the proteolytic contribution of tumor-associated macrophages(TAM)in tumor invasion,we analyzed whether TAM at the invasive front of small HCC in Abcb4-/--mice show an enhanced expression of MMP-9. METHODS:Liver cryosections of the hepatocellular carcinoma(HCC)invasive front from 12 mo old Abcb4-/--mice were stained for collagen typeⅠand MMP-9 using Alexa488 and Alexa568 labeled secondary ***,the Alexa568 dye was bleached and the macrophage marker F4/80 was visualized using Alexa568 labeled secondary ***, photographs of the invasive tumor front were digitally overlaid and analyzed. RESULTS:After complete bleaching of the primary dye,specific fluorescence staining of a third antigen, here F4/80,was successfully performed on the same histological *** this method,we were able to identify conglomerates of matrix metalloproteinase (MMP-9)expressing macrophages within the tumor capsule of HCC. CONCLUSION:MMP-9 expressing macrophages are involved in matrix remodelling at the invasive tumor front of *** described staining protocol provides a simple yet powerful extension of conventional immuno-histochemistry,facilitating visualization of at least three different antigens plus nuclei in one single histological section.

关键词： Fluorescence staining Hepatocellular carcinoma Matrix metalloproteinase Tumor associated macrophages

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针对复合材料加工的模块化仿真软件

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现代制造 2015年第21期 32-32页

作者： frank Engelhart timo Henkel

展望未来是一件好事。今天，金属切削领域通过采用基于软件的系统来识别编程的错误。而对于复合材料的预测，现在也有一种特殊的软件可以为我们提供帮助了。

关键词：仿真软件复合材料材料加工模块化金属切削

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欧洲中央银行（ECB）

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城市环境设计 2020年第4期 162-173页

作者：沃尔夫·狄·普瑞克斯 Magdalena Baczkowska Markus Baumann Michael Beckert Johannes Behrens Hilde Benda Marcelo Bernardi Nico Boyer Jan Brosch timo Carl Anna Rita Cedroni Jasmin Dieterle Sabrina Dlugosch Jan Ruben Fischer Brigitte Fuchs Sergio Gonzales Gesine G?rlich Martin Gruber Guthu Hallstein Sebastian Haffner Simone Hainz Sascha Hempel Rob Henderson Emanuele Iacono Martin Jelinek Rashmi Krishna Jois Ivana Jug frank Pascal Kaul Matt Kirkham Daniela Kr?hnert Bernward Krone Christian Labud Anke Lammert Monika Lyzyczka Steven M Christian Maeder Dimitra Mamou Ariane Marx Christoph Maurer Matthias Niemeyer Martin Oberascher Ross Olson Renate Ott Gerhard Pfeiler Ellen Pietrzyk James Pike Robert Pippan Jakob Przybylo Anna Ptaszynska Stephanie Rathgeber Carmen Renz Salome Reves Donna Riedel Akvile Rimantaite Pete Rose Penelope Rüttimann Stefan Rutzinger Oliver Sachse Kristina Schinegger Benjamin Schmidt Marita Schnepper Thomas Siegl Ebru Simsek-Lenk Denise Sokolowski Augustin Solorzano Anja Sorger Andrea St?llenwerk Ernst Stockinger Crystal K.H Tang Jürgen Tiltmann Markus Tritthart Josef Tr?ster Günther Weber Andreas Weissenbach Clemens Werb Judith Werkh?user Markus Wings Eva Wolf Barbara Zeleny Thomas Zengger Zeyneb Badur Fabien Barthelemey Oliver Cassik Alejandro Corena Alexander Daxb?ck Mario Dign?ss Helmut Fr?tscher Annegret Haider Christian Halm Gregor Kassl Gernot K?fer Alexander Laber Anita Lischka Rangel Malinov Oliver Martinz Philipp Munz Barbara Roller Nicole Rumpler Wolfgang Ruthensteiner Stefan Salchinger Stefan Schadenb?ck Thomas Schwed Hannes Schwed Eckart Schwerdtfeger Sylvia Spernbauer Christoph Treberspurg Johannes Weigl Paul Raftery European Central Bank/RobertMetsch Markus Pillhofer

项目大事记/CHRONOLOGY竞赛/Competition:第一阶段/Phase 1:2003;第二阶段/Phase 2:2003-2004;修改阶段/Revision Phase:2004;优化阶段/Optimization Phase:2005规划设计起始时间/Start of Planning:2005前期工程/Preliminary Site Works:2008主体施工/Main Construction Works:2010竣工/Completion:2014项目参数/PROJECT DATA用地面积/Site Area:120 000m2建筑毛面积/Gross Floor Area:185 000m2

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