AbnormalPTPN11enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation.
ThePTPN11gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis forPTPN11overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer inPTPN11intron 1, which contained a glucocorticoid receptor- binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS. RA FLS stimulation with the glucocorticoid dexamethasone induced GR binding to the enhancer andPTPN11expression. Glucocorticoid responsiveness ofPTPN11was significantly higher in RA FLS than OA FLS and required the differentially methylated CpGs for full enhancer function. SHP-2 expression was enriched in the RA synovial lining, and heterozygousPtpn11deletion in radioresistant or innate immune cells attenuated K/BxN serum transfer arthritis in mice. Treatment with SHP-2 inhibitor 11a-1 reduced RA FLS migration and responsiveness to TNF and IL-1β stimulation and reduced arthritis severity in mice. Our findings demonstrate how abnormal epigenetic regulation of a pathogenic gene determines FLS behavior and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for RA.
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA.
Keisuke
K
Maeshima
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Stephanie M
SM
Stanford
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA.
Deepa
D
Hammaker
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Cristiano
C
Sacchetti
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Li-Fan
LF
Zeng
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
Rizi
R
Ai
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Vida
V
Zhang
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA.
David L
DL
Boyle
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
German R
GR
Aleman Muench
Department of Pathology and Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
Gen-Sheng
GS
Feng
Janssen Pharmaceuticals Companies of Johnson and Johnson, La Jolla, California, USA.
John W
JW
Whitaker
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Zhong-Yin
ZY
Zhang
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
Wei
W
Wang
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA.; Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Nunzio
N
Bottini
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, California, USA.
Gary S
GS
Firestein