Evidence map›Paper›PMID 25995222›Full record

ArticleScience translational medicine2015

Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.

Karen M Doody, Stephanie M Stanford, Cristiano Sacchetti, Mattias N D Svensson, Charlotte H Coles, Nikolaos Mitakidis, William B Kiosses, Beatrix Bartok, Camille Fos, Esther Cory and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.

0numbers the graph read from it
0cells of the map it votes in
38citing papers in PubMed
2.1field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

38 citing papers in PubMed, 60 citations in OpenAlex.

  1. Structure-Based Engineering for PTPσ-Targeted Therapeutic Development.International journal of molecular sciences · 2026
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors at 5 institutions in 3 countries.

Karen M DoodyDivision of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Stephanie M StanfordDivision of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Cristiano SacchettiDivision of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Mattias N D SvenssonDivision of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Charlotte H ColesDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Nikolaos MitakidisDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
William B KiossesCore Microscopy, Scripps Research Institute, La Jolla, CA 92037, USA.
Beatrix BartokDivision of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
Camille FosDivision of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Esther CoryDepartment of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Robert L SahDepartment of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Ru Liu-BryanDivision 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.
David L BoyleDivision of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
Heather A ArnettInflammation Research, Amgen Washington, Seattle, WA 98119, USA.
Tomas MustelinResearch, MedImmune, AstraZeneca, One Medimmune Way, Gaithersburg, MD 20878, USA.
Maripat CorrDivision of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
Jeffrey D EskoDepartment of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
Michel L TremblayRosalind 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.
Gary S FiresteinDivision of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
A Radu AricescuDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Nunzio BottiniDivision of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. nunzio@lji.org.
La Jolla Institute for Immunology · USUniversity of California, San Diego · USUniversity of Oxford · GBCentre for Human Genetics · GBMcGill University · CA

Funding

UC San Diego Clinical and Translational Research InstituteUL1TR001442 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S, HOGARTH, MICHAEL · 2015 to 2024
$88.3M
TISSUE ACQUISITION, MORPHOLOGY, AND CELL CULTUREP01AG007996 · NIA · UNIVERSITY OF CALIFORNIA SAN DIEGO · PI SAH, ROBERT L · 1989 to 2016
$26.0M
San Diego Clinical and Translational Research InstituteUL1TR000100 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S · 2012 to 2015
$19.7M
Role of PTPRS in Rheumatoid ArtiritisR01AR066053 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BOTTINI, NUNZIO · 2014 to 2025
$4.0M
Regulation of p38 and inflammation by MAPK kinasesR01AI070555 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S · 2006 to 2016
$3.8M
c-Jun N-terminal kinase and joint destruction in RAR01AR047825 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S · 2002 to 2012
$2.7M
Drug Discovery for Multiple Hereditary ExostosesR01AR064202 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ESKO, JEFFREY D · 2013 to 2017
$1.9M
c-Jun N-terminal kinase and joint destruction in RAR55AR047825 · NIAMS · UNIVERSITY OF CALIFORNIA SAN DIEGO · PI FIRESTEIN, GARY STEVEN · 2001 to 2001
$100k
ATP-Citrate Lyase As A Novel Metabolic Target for OsteoarthritisI01BX002234 · VA · VA SAN DIEGO HEALTHCARE SYSTEM · PI BRYAN, RU · 2015 to 2022
–
BLRD VA I01 BX002234CIHRMedical Research Council MR/L009609/1NCATS NIH HHS UL1 TR000100NCATS NIH HHS UL1TR000100NCATS NIH HHS UL1 TR001442NIAID NIH HHS AI070555NIAID NIH HHS R01 AI070555NIAMS NIH HHS AR064202NIAMS NIH HHS AR066053NIAMS NIH HHS AR47825NIAMS NIH HHS R01 AR047825NIAMS NIH HHS R01 AR064202NIAMS NIH HHS R01 AR066053NIAMS NIH HHS R55 AR047825NIA NIH HHS P01 AG007996Wellcome Trust 090532
6 · The paper itself

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.

Indexed as

AnimalsAntirheumatic AgentsArthritis, RheumatoidCell AdhesionCell MovementChondroitin Sulfate ProteoglycansCytoskeletal ProteinsDisease Models, AnimalEzrinHEK293 CellsHeparinHumansMice, KnockoutMolecular Targeted TherapyPhosphorylationProteoglycansAntirheumatic AgentsChondroitin Sulfate ProteoglycansCytoskeletal ProteinsEzrinHeparinheparin proteoglycanProteoglycansPTPRS protein, humanPtprs protein, mouseReceptor-Like Protein Tyrosine Phosphatases, Class 2SDC4 protein, humanSdc4 protein, mouseSyndecan-4

Identifiers

PMID25995222
PMCPMC4458332
OpenAlexW2103794321

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.