Receptor protein tyrosine phosphatase alpha enhances rheumatoid synovial fibroblast signaling and promotes arthritis in mice

Stephanie M Stanford, Mattias N D Svensson, Cristiano Sacchetti, Caila A Pilo, Dennis J Wu, William B Kiosses, Annelie Hellvard, Brith Bergum, German R Aleman Muench, Christian Elly, Yun-Cai Liu, Jeroen den Hertog, Ari Elson, Jan Sap, Piotr Mydel, David L Boyle, Maripat Corr, Gary S Firestein, Nunzio Bottini

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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

METHODS: Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, invasion and migration in 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 Ptpra(-/-) 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 Y527 and decreased phosphorylation of FAK on stimulatory Y397. Treatment of RA FLS with an inhibitor of FAK phenocopied knockdown of RPTPα. Ptpra-deficient mice were protected from arthritis development, which was due to radioresistant cells.

CONCLUSIONS: By regulating phosphorylation of SRC and FAK, RPTPα mediates pro-inflammatory and pro-invasive signaling in RA FLS, correlating with promotion of disease in an FLS-dependent model of RA. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalArthritis and Rheumatology
Early online date28 Sep 2015
DOIs
Publication statusPublished - 25 Jan 2016

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