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Sci Transl Med. 2015 May 20;7(288):288ra76. doi: 10.1126/scitranslmed.aaa4616.

Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.

Author information

1
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
2
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
3
Core Microscopy, Scripps Research Institute, La Jolla, CA 92037, USA.
4
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
5
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
6
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA. Veterans Affairs San Diego Healthcare System, Department of Medicine, University of California, San Diego, San Diego, CA 92161, USA.
7
Inflammation Research, Amgen Washington, Seattle, WA 98119, USA.
8
Research, MedImmune, AstraZeneca, One Medimmune Way, Gaithersburg, MD 20878, USA.
9
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
10
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada. Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada. Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
11
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. nunzio@lji.org.

Abstract

Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients.

PMID:
25995222
PMCID:
PMC4458332
DOI:
10.1126/scitranslmed.aaa4616
[Indexed for MEDLINE]
Free PMC Article

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