title: Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.
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.
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Doody
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Sacchetti
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Mattias N D
authors.initials: MN
authors.lastname: Svensson
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Coles
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Mitakidis
authors.affiliation: Core Microscopy, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Bartok
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Fos
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Cory
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sah
authors.affiliation: 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.
authors.forename: Ru
authors.initials: R
authors.lastname: Liu-Bryan
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.affiliation: Inflammation Research, Amgen Washington, Seattle, WA 98119, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Arnett
authors.affiliation: Research, MedImmune, AstraZeneca, One Medimmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: 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.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: A Radu
authors.initials: AR
authors.lastname: Aricescu
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. nunzio@lji.org.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D000099149:Ezrin
chemical_list: D018501:Antirheumatic Agents; D011508:Chondroitin Sulfate Proteoglycans; D003598:Cytoskeletal Proteins; D006493:Heparin; D011509:Proteoglycans; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D053671:Syndecan-4; D000099149:Ezrin; C508304:SDC4 protein, human; C508306:Sdc4 protein, mouse; C036090:heparin proteoglycan; C516883:PTPRS protein, human; C516885:Ptprs protein, mouse