Research ArticleRheumatoid Arthritis

Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy

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Science Translational Medicine  20 May 2015:
Vol. 7, Issue 288, pp. 288ra76
DOI: 10.1126/scitranslmed.aaa4616

Switching off arthritis

In patients with rheumatoid arthritis (RA), joint-lining cells—fibroblast-like synoviocytes (FLS)—become activated and contribute to inflammation as well as cartilage and bone destruction. FLS express RPTPσ, which, in neurons, can be regulated by a proteoglycan switch. Doody et al. now find that FLS can also be regulated by this proteoglycan switch, and that an RPTPσ decoy protein can block this switch and decrease FLS invasiveness and severity of arthritis in human cells and a mouse model of RA. If these data hold true in humans, targeting this proteoglycan switch may add another option when treating patients with RA.


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.

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