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 RPTP?, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTP? 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 RPTP? decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTP? and the heparan sulfate proteoglycan syndecan-4. RPTP? mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTP? 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 RPTP?-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.

SUBMITTER: Doody KM 

PROVIDER: S-EPMC4458332 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature