# Role of PTPRS in Rheumatoid Arthritis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $457,330

## Abstract

ABSTRACT
Fibroblast-like synoviocytes (FLS) are joint-lining non-hematopoietic cells that in rheumatoid arthritis (RA)
contribute to local joint inflammation and damage. There is interest in discovering FLS-directed therapeutic
agents that could be combined with current immunosuppressant disease-modifying anti-rheumatic agents
(DMARDs). This renewal proposal focuses on understanding the mechanism of action and regulation of the
tyrosine phosphatase PTPRS, which plays a critical role in FLS migration and invasion.
In the first cycle of this grant, we have shown that PTPRS is an important regulator of FLS aggressiveness during
RA and developed an approach to modulate PTPRS function in rheumatoid FLS. Our studies showed that on
the surface of RA FLS, PTPRS is kept in an inactive state through specific binding to the heparan sulfate (HS)-
proteoglycan syndecan-4 through a mechanism called the proteoglycan switch. Treatment of RA FLS with a
decoy fragment of PTPRS encompassing its two most extracellular proteoglycan-binding immunoglobulin
domains (called Ig1&2) causes detachment of PTPRS from syndecan-4. This leads to PTPRS-dependent
inhibition of migration and invasiveness via dephosphorylation of the PTPRS substrate ezrin. In vivo
administration of Ig1&2 reverses arthritis in multiple mouse models via a non-immunological mechanism. We
also find that PTPRS expression is inhibited on RA FLS by tumor necrosis factor alpha, suggesting that PTPRS
expression is regulated by joint inflammation.
In the second cycle of the grant, we would like to deepen our knowledge of the mechanism of action and
regulation of PTPRS in FLS and RA. Here we propose to a series of mechanistic studies in primary human FLS
and mouse models of RA aimed at understanding the regulation of PTPRS expression in RA FLS (Aims 1) and
how Ig1&2 and PTPRS regulate FLS-induced inflammation in arthritis (Aim 2). We will also use biochemical,
structural, and cellular biology approaches to understand the key molecular determinants for PTPRS regulation
by syndecan-4 (Aim 3).
Our long-term goal remains to understand the biology of PTPRS in RA FLS, which will help to complete the
validation of the PTPRS-regulated pathway as a therapeutic target for RA.

## Key facts

- **NIH application ID:** 10705192
- **Project number:** 5R01AR066053-08
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Nunzio Bottini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $457,330
- **Award type:** 5
- **Project period:** 2014-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705192

## Citation

> US National Institutes of Health, RePORTER application 10705192, Role of PTPRS in Rheumatoid Arthritis (5R01AR066053-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10705192. Licensed CC0.

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