Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions.
A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.
Mojca
M
Frank-Bertoncelj
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.
Michelle
M
Trenkmann
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.
Kerstin
K
Klein
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.
Emmanuel
E
Karouzakis
Functional Genomics Center Zurich, ETH Zurich and University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Hubert
0000-0001-7612-9394
H
Rehrauer
Functional Genomics Center Zurich, ETH Zurich and University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Anna
A
Bratus
Schulthess Clinic, Lengghalde 2, 8008 Zurich, Switzerland.
Christoph
C
Kolling
Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', 34, Fleming Street, 16672 Vari, Attica, Greece.
Maria
M
Armaka
Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
Andrew
A
Filer
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.
Beat A
BA
Michel
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.
Renate E
RE
Gay
Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
Christopher D
CD
Buckley
Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', 34, Fleming Street, 16672 Vari, Attica, Greece.|Department of Experimental Physiology, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Goudi, Athens, Greece.
George
G
Kollias
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.|Center of Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Steffen
S
Gay
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, 8952 Schlieren, Zurich, Switzerland.|Center of Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Caroline
C
Ospelt
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019175:DNA Methylation; D057890:Epigenomics; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D042421:Histone Code; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007596:Joints / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*
D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; C071250:TLX1 protein, human