Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy

Autor: Beatrix Bartok, William B. Kiosses, Nikolaos Mitakidis, Nunzio Bottini, David L. Boyle, Jeffrey D. Esko, Mattias Svensson, Gary S. Firestein, Ru Liu-Bryan, Esther Cory, Camille Fos, Stephanie M. Stanford, Robert L. Sah, Tomas Mustelin, Heather A. Arnett, C.H. Coles, Michel L. Tremblay, Karen M. Doody, Maripat Corr, Cristiano Sacchetti, A. Radu Aricescu
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Time Factors
deficiency [Receptor-Like Protein Tyrosine Phosphatases
Class 2]

Arthritis
Receptor-Like Protein Tyrosine Phosphatases
Protein tyrosine phosphatase
metabolism [Syndecan-4]
Medical and Health Sciences
metabolism [Cytoskeletal Proteins]
Severity of Illness Index
Arthritis
Rheumatoid

PTPRS protein
human

chemistry.chemical_compound
Mice
0302 clinical medicine
Cell Movement
Rheumatoid
drug effects [Cell Adhesion]
analogs & derivatives [Heparin]
2.1 Biological and endogenous factors
Molecular Targeted Therapy
Phosphorylation
skin and connective tissue diseases
drug effects [Cell Movement]
Mice
Knockout

0303 health sciences
biology
metabolism [Proteoglycans]
Synovial Membrane
Receptor-Like Protein Tyrosine Phosphatases
Class 2

General Medicine
Heparan sulfate
Biological Sciences
musculoskeletal system
3. Good health
Cell biology
medicine.anatomical_structure
drug effects [Synovial Membrane]
Antirheumatic Agents
immunology [Synovial Membrane]
pharmacology [Antirheumatic Agents]
SDC4 protein
human

Proteoglycans
ddc:500
Signal transduction
Signal Transduction
musculoskeletal diseases
drug effects [Signal Transduction]
Knockout
Rheumatoid Arthritis
Transfection
Autoimmune Disease
pathology [Synovial Membrane]
Ptprs protein
mouse

03 medical and health sciences
genetics [Syndecan-4]
metabolism [Receptor-Like Protein Tyrosine Phosphatases
Class 2]

medicine
Cell Adhesion
Animals
Humans
enzymology [Arthritis
Rheumatoid]

Chondroitin sulfate
enzymology [Synovial Membrane]
immunology [Arthritis
Rheumatoid]

030304 developmental biology
metabolism [Heparin]
antagonists & inhibitors [Receptor-Like Protein Tyrosine Phosphatases
Class 2]

Animal
Heparin
Cartilage
Inflammatory and immune system
genetics [Receptor-Like Protein Tyrosine Phosphatases
Class 2]

pathology [Arthritis
Rheumatoid]

Class 2
heparin proteoglycan
medicine.disease
Sdc4 protein
mouse

prevention & control [Arthritis
Rheumatoid]

ezrin
carbohydrates (lipids)
Disease Models
Animal

Cytoskeletal Proteins
HEK293 Cells
Proteoglycan
chemistry
Chondroitin Sulfate Proteoglycans
Musculoskeletal
Immunology
Disease Models
biology.protein
Syndecan-4
metabolism [Chondroitin Sulfate Proteoglycans]
030217 neurology & neurosurgery
Zdroj: Science translational medicine 7(288), 288ra76-288ra76 (2015). doi:10.1126/scitranslmed.aaa4616
Science translational medicine, vol 7, iss 288
DOI: 10.1126/scitranslmed.aaa4616
Popis: 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.
Databáze: OpenAIRE