Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy

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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

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Karen M Doody1, Stephanie M Stanford1, Cristiano Sacchetti1

  • 1Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

Science Translational Medicine
|May 22, 2015
PubMed

Insights

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) are regulated by a proteoglycan switch involving RPTPσ. Targeting this pathway with RPTPσ decoy proteins reduced FLS invasiveness and arthritis severity in RA models.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Immunology

Background:

  • Rheumatoid arthritis (RA) treatments often fail to induce remission in many patients.
  • Fibroblast-like synoviocytes (FLS) drive joint inflammation and destruction in RA.
  • Novel therapeutic targets for FLS are needed to improve RA treatment outcomes.

Purpose of the Study:

  • To identify and validate RPTPσ as a therapeutic target for FLS-directed RA therapy.
  • To investigate the role of the proteoglycan switch in regulating FLS function.
  • To evaluate the efficacy of targeting the RPTPσ pathway in preclinical RA models.

Main Methods:

  • Investigated the interaction between RPTPσ and proteoglycans (chondroitin sulfate, heparan sulfate).
  • Utilized a proteoglycan-binding RPTPσ decoy protein to inhibit FLS invasiveness and attachment.
  • Assessed the impact of RPTPσ on FLS signaling pathways, including ezrin phosphorylation.
  • Evaluated the therapeutic potential of the RPTPσ decoy protein in a K/BxN serum transfer model of RA.

Main Results:

  • RPTPσ function in FLS is regulated by a proteoglycan switch mechanism.
  • Disruption of RPTPσ-syndecan-4 interaction using a decoy protein inhibited FLS invasiveness and cartilage attachment.
  • RPTPσ mediates proteoglycan effects on FLS signaling via ezrin regulation.
  • In vivo administration of the RPTPσ decoy protein reduced FLS invasiveness and RA severity.

Conclusions:

  • FLS function in RA is controlled by an RPTPσ-dependent proteoglycan switch.
  • Targeting the proteoglycan switch or its downstream signaling offers a potential therapeutic strategy for RA.
  • RPTPσ-targeted therapies could be used as monotherapy or in combination with existing RA treatments to enhance disease control.

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