Background/Purpose:   RPTPσ (gene PTPRS) is a protein tyrosine phosphatase that binds heparan sulfate- and chondroitin sulfate-containing proteoglycans with its extracellular immunoglobulin domains 1 and 2 (Ig1&2). RPTPσ is expressed at minimal or low levels in immune cells, while in neurons the competition between heparan sulfate and chondroitin sulfate for RPTPσ binding controls axon outgrowth and is called the proteoglycan switch. We recently reported that RPTPσ is highly expressed in fibroblast-like synoviocytes (FLS) and the proteoglycan switch exists in these cells. Treatment of FLS with decoy RPTPσ Ig1&2 competes with surface heparan sulfate proteoglycans, which flips the proteoglycan switch and reduces rheumatoid arthritis (RA) FLS migration, invasion and attachment to cartilage. Systemic administration of RPTPσ Ig1&2 reduces arthritis severity and cartilage damage in the K/BxN serum transfer mouse model of RA. To further characterize RPTPσ Ig1&2 as a putative FLS-targeting treatment for RA, we tested its selectivity for FLS, as well as its effectiveness in an additional mouse model of arthritis.

Methods: Migration was assessed using a scratch-wound assay with RA FLS and normal human dermal fibroblasts (NHDF). Collagen production in NHDF was assessed by measuring collagen 1A2 mRNA expression in TGFβ-stimulated cells. RPTPσ  and heparan sulfate proteoglycan mRNA expression were measured by qPCR. Surface expression of heparan sulfate was assessed by flow cytometry. Collagen antibody-induced arthritis (CAIA) was induced by injection of mice with an anti-collagen antibody cocktail (ArthritoMab®).

Results:  RPTPσ Ig1&2 decreased migration of RA FLS by 27%, but did not affect migration of NHDF. This was not due to differences in PTPRS expression; however, surface heparan sulfate levels and expression of heparan sulfate proteoglycans were higher in RA FLS (> 4-fold and > 2-fold increase, respectively). RPTPσ Ig1&2 did not affect collagen production by NHDF upon TGFβ stimulation, a characteristic function of these cells important for wound-healing. Finally, RPTPσ Ig1&2 administration decreased arthritis severity by 30% in the CAIA mouse model of RA.

Conclusion: RPTPσ Ig1&2 treatment ameliorates arthritis in multiple models by selectively targeting FLS due to their high expression of heparan sulfate proteoglycans. These results support further testing of RPTPσ Ig1&2 alone and in combination with conventional immune-targeting RA therapies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterizing-the-rptp-mediated-proteoglycan-switch-as-a-target-for-rheumatoid-arthritis-therapy/