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Arthritis Rheumatol. 2016 Feb;68(2):359-69. doi: 10.1002/art.39442.

Receptor Protein Tyrosine Phosphatase α-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice.

Author information

1
La Jolla Institute for Allergy and Immunology, La Jolla, California.
2
The Scripps Research Institute, La Jolla, California.
3
Broegelmann Research Laboratory and University of Bergen, Bergen, Norway.
4
Hubrecht Institute-Koninklijke Nederlands Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands, and Institute of Biology, Leiden, The Netherlands.
5
Weizmann Institute of Science, Rehovot, Israel.
6
Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
7
University of California at San Diego School of Medicine, La Jolla.

Abstract

OBJECTIVE:

During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the extracellular matrix of the joint. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to the anomalous behavior of RA FLS. The receptor protein tyrosine phosphatase α (RPTPα), which is encoded by the PTPRA gene, is a key promoter of FAK signaling. The aim of this study was to investigate whether RPTPα mediates FLS aggressiveness and RA pathogenesis.

METHODS:

Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction analysis and enzyme-linked immunosorbent assay, invasion and migration by Transwell assays, survival by annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in RPTPα-knockout (KO) mice using the K/BxN serum-transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone marrow transplantation.

RESULTS:

RPTPα was enriched in the RA synovial lining. RPTPα knockdown impaired RA FLS survival, spreading, migration, invasiveness, and responsiveness to platelet-derived growth factor, tumor necrosis factor, and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of Src on inhibitory Y(527) and decreased phosphorylation of FAK on stimulatory Y(397) . Treatment of RA FLS with an inhibitor of FAK phenocopied the knockdown of RPTPα. RPTPα-KO mice were protected from arthritis development, which was due to radioresistant cells.

CONCLUSION:

By regulating the phosphorylation of Src and FAK, RPTPα mediates proinflammatory and proinvasive signaling in RA FLS, correlating with the promotion of disease in an FLS-dependent model of RA.

PMID:
26414708
PMCID:
PMC4770259
DOI:
10.1002/art.39442
[Indexed for MEDLINE]
Free PMC Article

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