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1. Molecular maps of synovial cells in inflammatory arthritis using an optimized synovial tissue dissociation protocol

Author

Sam G. Edalat, Reto Gerber, Miranda Houtman, Janine Lückgen, Rui Lourenço Teixeira, Maria del Pilar Palacios Cisneros, Tamara Pfanner, Tadeja Kuret, Nadja Ižanc, Raphael Micheroli, Joaquim Polido-Pereira, Fernando Saraiva, Swathi Lingam, Kristina Burki, Blaž Burja, Chantal Pauli, Žiga Rotar, Matija Tomšič, Saša Čučnik, João Eurico Fonseca, Oliver Distler, Ângelo Calado, Vasco C. Romão, Caroline Ospelt, Snežna Sodin-Semrl, Mark D. Robinson, and Mojca Frank Bertoncelj

Subjects
Health sciences, Technical aspects of cell biology, Omics, Transcriptomics, Science
Abstract

Summary: In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

Published
2024
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3. Contributors

Author

Engy Abdellatif, Aryeh M. Abeles, Abby G. Abelson, Abhishek Abhishek, Steven B. Abramson, Jonathan D. Adachi, Michael A. Adams, Thomas Aigner, Shizuo Akira, Daniel Aletaha, Antonios O. Aliprantis, Adriana Almeida de Jesus, Roy D. Altman, Mary-Carmen Amigo, Martin Aringer, Dana P. Ascherman, Shervin Assassi, Sergei P. Atamas, Pedro Ming Azevedo, Alan N. Baer, Dominique Baeten, Colin Baines, Nancy A. Baker, Emese Balogh, Alejandro Balsa, Xenofon Baraliakos, Thomas Bardin, Les Barnsley, Joan M. Bathon, Angela Bauch, Jill J.F. Belch, Nicholas Bellamy, Teresita Bellido, Michael Benjamin, Michael W. Beresford, Brian Berman, Bonnie Lee Bermas, George Bertsias, John P. Bilezikian, Yelda Bilginer, Julius Birnbaum, Felicity L. Bishop, Jane F. Bleasel, Markus Böhm, Marcy B. Bolster, Stefano Bombardieri, Michael Bonelli, Sydney L. Bonnick, Dimitrios T. Boumpas, Aline Bozec, Richard D. Brasington, Juergen Braun, Matthew A. Brown, Ian N. Bruce, William D. Bugbee, Marwan A.S. Bukhari, Rubén Burgos-Vargas, Gerd-Rüdiger Burmester, Jane C. Burns, David B. Burr, Frank Buttgereit, Vivian P. Bykerk, Leonard H. Calabrese, Jeffrey P. Callen, Sabrina Cavallo, Tim E. Cawston, Vinod Chandran, Michael Denis Chard, Prateek Chaudhary, Lan X. Chen, Hyon K. Choi, Ernest H. Choy, Lisa Christopher-Stine, Alvina D. Chu, Daniel J. Clauw, Philip J. Clements, Megan E.B. Clowse, J. Gerry Coghlan, Philip G. Conaghan, Cyrus Cooper, Karen H. Costenbader, Paul Creamer, José C. Crispín, Bruce N. Cronstein, Raymond Cross, Natalie E. Cusano, Maurizio Cutolo, Chris D'Adamo, Vivette D'Agati, David P. D'Cruz, Hanne Dagfinrud, David I. Daikh, Nicola Dalbeth, Seamus E. Dalton, Shouvik Dass, Aileen M. Davis, Karel De Ceulaer, Chad L. Deal, Kevin D. Deane, Alessandra Della Rossa, Paul F. Dellaripa, Elaine Dennison, Christopher P. Denton, Paul Dieppe, Michael Doherty, Patricia Dolan, Rachelle Donn, Olga Dvorkina, George S.M. Dyer, Richard Eastell, N. Lawrence Edwards, Paul Emery, Gurhan Erturan, Luis R. Espinoza, Steve Eyre, Antonios C. Fanouriakis, Joshua Farber, Shawn Farrokhi, Anders Fasth, Eugen Feist, Debbie Feldman, David T. Felson, John D. Fisk, G. Kelley Fitzgerald, Raymond H. Flores, David A. Fox, Clair A. Francomano, Jennifer Frangos, Anthony J. Freemont, Kevin B. Fricka, Daniel E. Furst, Cem Gabay, Massimo Gadina, J.S. Hill Gaston, Steffen Gay, Lianne S. Gensler, Laura Geraldino-Pardilla, Danielle M. Gerlag, Ellen M. Ginzler, Alison M. Gizinski, Dafna D. Gladman, Garry E. Gold, Raphaela Goldbach-Mansky, Sarah Goldingay, Sharon M. Gordon, Rachel Gorodkin, Jörg J. Goronzy, Simon Görtz, Rodney Grahame, Andrew J. Grainger, Ellen M. Gravallese, Jeffrey D. Greenberg, Bansari Gujar, Matilda Hagan, Karlene Hagley, Alan J. Hakim, John C. Hall, Vedat Hamuryudan, John G. Hanly, Eric P. Hanson, Boulos Haraoui, John B. Harley, Philip J. Hashkes, Gillian A. Hawker, Philip N. Hawkins, Turid Heiberg, Dick Heinegård, Simon M. Helfgott, Pauline Y.P. Ho, Marc C. Hochberg, Jacqueline Hochman, Chelsea J. Hodgkiss-Harlow, Robert W. Hoffman, Markus Hoffmann, V. Michael Holers, Michael F. Holick, Christopher Holroyd, Osvaldo Hübscher, David J. Hunter, M. Elaine Husni, Robert D. Inman, Zacharia Isaac, Maura D. Iversen, Douglas A. Jabs, William Jackson, Sarada Jaimungal, Judith A. James, Rose-Marie Javier, Alyssa K. Johnsen, Joanne M. Jordan, Tsuneyasu Kaisho, Cees G.M. Kallenberg, David Kane, Mohit Kapoor, Elizabeth W. Karlson, Dimitrios G. Kassimos, Daniel L. Kastner, Jeffrey N. Katz, Jonathan Kay, Jennifer A. Kelly, Edward Keystone, Munther A. Khamashta, Dinesh Khanna, Ingvild Kjeken, Alisa E. Koch, Matthew F. Koff, Leah Kottyan, Loukia A. Koutsogeorgopoulou, Virginia Byers Kraus, Pradeep Kumar, Tore K. Kvien, Robert Lafyatis, Robert B.M. Landewé, Carol A. Langford, Arthur N. Lau, Ronald M. Laxer, Thomas J. Learch, George Lewith, Yi Li, Katherine P. Liao, Geoffrey Littlejohn, Pilar Lorenzo, Thomas A. Luger, Ingrid E. Lundberg, Karin Lundberg, Klaus P. Machold, C. Ronald MacKenzie, Alfred D. Mahr, Eric Manheimer, Joan C. Marini, Javier Marquez, Debbie Marsden, Johanne Martel-Pelletier, Emilio Martín-Mola, Manuel Martínez-Lavín, Elena M. Massarotti, Eric L. Matteson, Stephen J. Matzat, Reza Mayahi, Maureen Davidica Mayes, Timothy McAlindon, Hayley McBain, Bill McCarberg, Edward F. McCarthy, Geraldine McCarthy, Michael F. McDermott, Dennis McGonagle, Lachy McLean, Peter A. Merkel, Jamal A. Mikdashi, Frederick W. Miller, Paul D. Miller, Kirsten Minden, Paul A. Monach, Kathleen Mulligan, Gauthier Namur, Esperanza Naredo, Kim E. Naylor, Amanda E. Nelson, Stanton P. Newman, Ellen Nordal, Ulrich Nöth, Eleana Ntatsaki, John J. O'Shea, Chester V. Oddis, Alejandro Olivé, Mohammed A. Omair, Michael J. Ombrello, Antonina Omisade, Voon H. Ong, Patrik Önnerfjord, Philippe Orcel, Caroline Ospelt, Seza Ozen, Stephen A. Paget, Dipak R. Patel, Carlo Patrono, Jean-Pierre Pelletier, Rosa Maria Rodrigues Pereira, Clarissa A. Pilkington, Michael H. Pillinger, Carlos Pineda, Robert M. Plenge, Andrew Price, Luminita Pricop, Lars Rackwitz, Angelo Ravelli, Anthony C. Redmond, Westley H. Reeves, Elaine F. Remmers, Luis Requena, Clio Ribbens, Bruce C. Richardson, Elena Riera Alonso, Graham Riley, Christopher Ritchlin, Susan Y. Ritter, Ivan O. Rosas, Drew D. Rowan, Martin Rudwaleit, Marina Rull, Marite Rygg, Kenneth G. Saag, Jane E. Salmon, Donald M. Salter, Daniel J. Salzberg, Philip N. Sambrook, Tore Saxne, Hans-Georg Schaible, Jose U. Scher, Georg Schett, Nicole Schmitz, Benjamin Schreiber, H. Ralph Schumacher, Daniella Muallem Schwartz, David G.I. Scott, Margaret Seton, Lauren M. Shapiro, Nancy Sharby, Jeffrey Siegel, Richard M. Siegel, Joachim Sieper, Richard M. Silver, Shonni J. Silverberg, Julia F. Simard, Barry P. Simmons, Robert W. Simms, Nora G. Singer, Malcolm D. Smith, Stacy E. Smith, Josef S. Smolen, Tim D. Spector, Virginia D. Steen, Allen C. Steere, Günter Steiner, Andre F. Steinert, George Stojan, John H. Stone, Vibeke Strand, Rainer H. Straub, Elizabeth A. Streeten, Giulio Superti-Furga, Deborah P.M. Symmons, Zoltan Szekanecz, Paul P. Tak, Antonio Tavoni, Peter C. Taylor, Robert Terkeltaub, Sarah S. Thomas, Jennifer E. Thorne, Jonathan H. Tobias, Adriana H. Tremoulet, George C. Tsokos, Rocky S. Tuan, Carl Turesson, Sebastian H. Unizony, Ana M. Valdes, Wim B. van den Berg, Désirée van der Heijde, Ronald Frits van Vollenhoven, John Varga, Dimitrios Vassilopoulos, Edward M. Vital, Karen Walker-Bone, Daniel J. Wallace, Gary Warburton, Robert J. Ward, Richard Watts, Mihir D. Wechalekar, Lucy R. Wedderburn, Michael E. Weinblatt, Matthew R. Weir, Claire Y.J. Wenham, Sterling G. West, Cornelia M. Weyand, Kenneth E. White, Kevin L. Winthrop, John B. Wong, Anthony D. Woolf, Jane Worthington, Huji Xu, Hasan Yazici, D.A. Young, Sebahattin Yurdakul, Yuqing Zhang, and Haoyang Zhuang

Published
2015

4. Epigenetics in rheumatology

Author

Caroline Ospelt and Steffen Gay

Subjects
medicine.medical_specialty, Family medicine, Internal medicine, medicine, Epigenetics, Biology, Rheumatology
Published
2015

5. Epigenetics

Author

Caroline Ospelt and Steffen Gay

Published
2013

6. Contributors

Author

Steven B. Abramson, Kai-Nan An, Felipe Andrade, John P. Atkinson, Dominique Baeten, Robert P. Baughman, Dorcas E. Beaton, Robert Bennett, Susanne M. Benseler, George Bertsias, Nina Bhardwaj, Johannes W.J. Bijlsma, Linda K. Bockenstedt, Maarten Boers, Francesco Boin, Dimitrios T. Boumpas, Barry Bresnihan, Doreen B. Brettler, Christopher D. Buckley, Ralph C. Budd, Christopher M. Burns, Amy C. Cannella, Eliza F. Chakravarty, Christopher Chang, Joseph S. Cheng, Christopher P. Chiodo, Leslie G. Cleland, Megan E. Clowse, Paul P. Cook, Joseph E. Craft, Leslie J. Crofford, Bruce N. Cronstein, Mary K. Crow, Gaye Cunnane, John J. Cush, Maurizio Cutolo, Maria Dall'Era, Kathryn H. Dao, Erika Darrah, John M. Davis, Jeroen DeGroot, Clint Devin, Betty Diamond, Federico Díaz-González, Paul E. Di Cesare, Rajiv Dixit, Joost P.H. Drenth, Michael L. Dustin, Hani S. El-Gabalawy, Keith B. Elkon, Doruk Erkan, Antonios Fanouriakis, Max Field, Andrew Filer, Gary S. Firestein, Oliver Fitzgerald, John P. Flaherty, Adrienne M. Flanagan, Karen A. Fortner, Sherine E. Gabriel, J.S. Hill Gaston, Steffen Gay, M. Eric Gershwin, Allan Gibofsky, Mark H. Ginsberg, Mary B. Goldring, Steven R. Goldring, Yvonne M. Golightly, Stuart Goodman, Siamon Gordon, Walter Grassi, Adam Greenspan, Peter K. Gregersen, Christine Grimaldi, Rula A. Hajj-Ali, Lorraine Harper, Edward D. Harris, Dominik R. Haudenschild, David B. Hellmann, Rikard Holmdahl, Joyce J. Hsu, James I. Huddleston, Thomas W.J. Huizinga, Gene G. Hunder, Emily W. Hung, Robert D. Inman, Maura Daly Iversen, Johannes W.G. Jacobs, Joanne M. Jordan, Joseph L. Jorizzo, Kenton R. Kaufman, William S. Kaufman, Arthur Kavanaugh, Robert T. Keenan, Shaukat Khan, Alisa E. Koch, Dwight H. Kono, Deborah Krakow, Robert G.W. Lambert, Robert B.M. Landewé, Nancy E. Lane, Carol A. Langford, Daniel M. Laskin, Ronald M. Laxer, David M. Lee, Lela A. Lee, Tzielan Chang Lee, Michael D. Lockshin, Rik Lories, Carlos J. Lozada, Ingrid E. Lundberg, Raashid Luqmani, Frank P. Luyten, Reuven Mader, Walter P. Maksymowych, Brian Mandell, Scott David Martin, Eric L. Matteson, Matthew J. McGirt, Iain B. McInnes, Elizabeth Kaufman McNamara, Ted R. Mikuls, Mark S. Miller, Kevin G. Moder, Kanneboyina Nagaraju, Stanley J. Naides, Amanda E. Nelson, Peter A. Nigrovic, Kiran Nistala, Johannes Nowatzky, James R. O'Dell, Yasunori Okada, Nataly Manjarrez Orduño, Caroline Ospelt, Mikkel Østergaard, Bradley M. Palmer, Richard S. Panush, Stanford L. Peng, Michael H. Pillinger, Gregory R. Polston, Steven A. Porcelli, Mark D. Price, Johannes J. Rasker, John D. Reveille, W. Neal Roberts, Monika Ronneberger, Antony Rosen, James T. Rosenbaum, Andrew E. Rosenberg, Eric M. Ruderman, Merja Ruutu, Jane E. Salmon, Jonathan Samuels, Christy I. Sandborg, Caroline O.S. Savage, Amit Saxena, Jose U. Scher, Georg Schett, David C. Seldin, Anna Simon, Dawd S. Siraj, Martha Skinner, E. William St. Clair, Lisa K. Stamp, John H. Stone, Rainer H. Straub, Susan E. Sweeney, Nadera J. Sweiss, Carrie R. Swigart, Deborah Symmons, Zoltan Szekanecz, Paul-Peter Tak, Peter C. Taylor, Robert Terkeltaub, Argyrios N. Theofilopoulos, Ranjeny Thomas, Thomas S. Thornhill, Karina D. Torralba, Michael J. Toth, Peter Tugwell, Zuhre Tutuncu, Katherine S. Upchurch, Désirée M.F.M. van der Heijde, Annette H.M. van der Helm-van Mil, Sjef M. van der Linden, Jos W.M. van der Meer, Jacob M. van Laar, John Varga, Mark S. Wallace, David M. Warshaw, Lucy R. Wedderburn, Victoria P. Werth, Fredrick M. Wigley, Christopher M. Wise, David Wofsy, Frederick Wolfe, Frank A. Wollheim, Robert L. Wortmann, Edward Yelin, David Yu, John B. Zabriskie, Robert B. Zurier, and Anne-Marie Zuurmond

Published
2013

8. Contributors

Author

Daniel Aletaha, Lars Alfredsson, Marina Backhaus, Joan M. Bathon, Johannes W.J. Bijlsma, Maarten Boers, Ferdinand C. Breedveld, Gerd R. Burmester, Nicholas D. Bushar, Frank Buttgereit, Philip G. Conaghan, Shouvik Dass, Kevin D. Deane, Thomas Dörner, Paul Emery, John M. Esdaile, Donna L. Farber, Jane E. Freeston, Steffen Gay, Daniëlle M. Gerlag, Mary B. Goldring, Mavis Goycochea, Désirée van der Heijde, Marc C. Hochberg, V. Michael Holers, Axel J. Hueber, Tom W.J. Huizinga, Alyssa K. Johnsen, Arthur Kavanaugh, Edward Keystone, Hans P. Kiener, Raimund W. Kinne, Lars Klareskog, Gisela Kobelt, Alisa E. Koch, Joel Kremer, Tore K. Kvien, Diane Lacaille, Robert Landewe, David M. Lee, Peter E. Lipsky, Klaus P. Machold, C. Ronald MacKenzie, Eric L. Matteson, Iain B. McInnes, Christopher G. Meyer, Toru Mima, Hoda Mirjafari, Larry W. Moreland, Kamal D. Moudgil, Peter A. Nigrovic, Norihiro Nishimoto, Sarah Okada, Francesca I. Okoye, Jacqueline E. Oliver, Caroline Ospelt, Stephen A. Paget, Saparna Pai, Thomas Pap, Dimitrios A. Pappas, Sarah Kaprove Penn, Robert M. Plenge, Jana Posalski, Rajesh Rajaiah, Kurt Redlich, Johan Rönnelid, Clemens Scheinecker, Georg Schett, David L. Scott, Jeffrey N. Siegel, Alan J. Silman, Lee S. Simon, Jasvinder A. Singh, Josef S. Smolen, Daniel H. Solomon, E. William St. Clair, Günter Steiner, Vibeke Strand, Bruno Stuhlmüller, Deborah Symmons, Zoltán Szekanecz, Paul Peter Tak, Peter C. Taylor, Ranjeny Thomas, Carl Turesson, Edward M. Vital, Michael M. Ward, Deborah Weber, Michael E. Weinblatt, Michael H. Weisman, Sterling G. West, Kevin L. Winthrop, Angela Zink, and Nathan J. Zvaifler

Published
2009

9. The role of resident synovial cells in destructive arthritis

Author

Caroline Ospelt, Steffen Gay, University of Zurich, and Gay, S

Subjects
Chemokine, 2745 Rheumatology, Arthritis, 610 Medicine & health, Proinflammatory cytokine, Epigenesis, Genetic, Arthritis, Rheumatoid, Mice, Immune system, Rheumatology, Proto-Oncogenes, medicine, Animals, Humans, Innate immune system, biology, business.industry, Synovial Membrane, 10051 Rheumatology Clinic and Institute of Physical Medicine, Fibroblasts, medicine.disease, Destructive Arthritis, Disease Models, Animal, medicine.anatomical_structure, Synovial Cell, 10076 Center for Integrative Human Physiology, Immunology, biology.protein, 570 Life sciences, Synovial membrane, business
Abstract

Infiltration by inflammatory cells, thickening of the lining layer, and destructive invasion into cartilage and bone are pathognomic features of the synovium in rheumatoid arthritis (RA). However, the most common cell types at the sites of invasion are resident cells of the joint, in particular synovial fibroblasts. These cells differ from healthy synovial fibroblasts in their morphology, their expression of proto-oncogenes and antiapoptotic molecules, and in their lack of certain tumor suppressor genes. Through their production of proinflammatory cytokines and chemokines mediated by signaling via Toll-like receptors, they are not only effector cells but also active parts of the innate immune system attracting inflammatory immune cells to the synovium. Most importantly, by producing matrix-degrading molecules they contribute strongly to the destructive mechanisms operative in RA.

Published
2008
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10. Epigenetic clues to rheumatoid arthritis

Author

Olga Sánchez-Pernaute, Caroline Ospelt, Michel Neidhart, Steffen Gay, University of Zurich, and Sánchez-Pernaute, O

Subjects
Immunology, Arthritis, 610 Medicine & health, Autoimmunity, Biology, medicine.disease_cause, Immune tolerance, Epigenesis, Genetic, Arthritis, Rheumatoid, Histones, medicine, Immune Tolerance, Immunology and Allergy, Gene silencing, Animals, Humans, Epigenetics, Gene Silencing, Regulation of gene expression, Inflammation, 2403 Immunology, Innate immune system, 10051 Rheumatology Clinic and Institute of Physical Medicine, Peripheral tolerance, DNA Methylation, Fibroblasts, medicine.disease, 2723 Immunology and Allergy, Cytokines
Abstract

The innate immune response needs to be tightly regulated to balance elimination of microorganisms with the magnitude of inflammation. The rupture of this balance is crucial for the outcome of diseases such as rheumatoid arthritis (RA) in which an overflowed proinflammatory response is associated with self-damage. Epigenetics alludes to systems controlling gene expression and silencing independent of the germline, but stable enough to be inherited by daughter cells upon mitosis. We will show in this review how pathological processes in RA can be shaped by epigenetics, which may in turn explain differences in phenotypes between subgroups of patients and also between subsets of fibroblasts within the joint. On the whole, the concourse of epigenetic mechanisms can precipitate the aggressive behaviour of cells and the rupture of peripheral tolerance. Targeting these emerging regulatory pathways is a promising approach for RA therapeutics.

Published
2008
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