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: 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, Robert L Sah, Ru Liu-Bryan, David L Boyle, Heather A Arnett, Tomas Mustelin, Maripat Corr, Jeffrey D Esko, Michel L Tremblay, Gary S Firestein, A Radu Aricescu, Nunzio Bottini
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 288 Pg. 288ra76 (May 20 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 25995222 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Antirheumatic Agents
• Chondroitin Sulfate Proteoglycans
• Cytoskeletal Proteins
• Proteoglycans
• SDC4 protein, human
• Sdc4 protein, mouse
• Syndecan-4
• ezrin
• heparin proteoglycan
• Heparin
• PTPRS protein, human
• Ptprs protein, mouse
• Receptor-Like Protein Tyrosine Phosphatases, Class 2

Topics

• Animals
• Antirheumatic Agents (pharmacology)
• Arthritis, Rheumatoid (enzymology, immunology, pathology, prevention & control)
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Chondroitin Sulfate Proteoglycans (metabolism)
• Cytoskeletal Proteins (metabolism)
• Disease Models, Animal
• HEK293 Cells
• Heparin (analogs & derivatives, metabolism)
• Humans
• Mice, Knockout
• Molecular Targeted Therapy
• Phosphorylation
• Proteoglycans (metabolism)
• Receptor-Like Protein Tyrosine Phosphatases, Class 2 (antagonists & inhibitors, deficiency, genetics, metabolism)
• Severity of Illness Index
• Signal Transduction (drug effects)
• Syndecan-4 (genetics, metabolism)
• Synovial Membrane (drug effects, enzymology, immunology, pathology)
• Time Factors
• Transfection