Fibroblast-like synoviocytes (FLS) are key players in mediating inflammation and joint destruction in rheumatoid arthritis (RA). There is an increased level of attention to this cell type as the possible target of a new generation of anti-RA therapie, which would be used in combination with immunomodulators to help control disease without increasing immune-suppression. The behavior of FLS is controlled by multiple interconnected signal transduction pathways. Several of these pathways involve reversible phosphorylation of proteins on tyrosine residues, which is the result of the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs). PTKs are well-known to be key mediators of FLS growth and invasiveness, and more recently, they are emerging as promising drug targets for RA. On the other hand, almost no work has been done on the PTPs in FLS. This grant application focuses on a transmembrane PTP called PTPRS. PTPRS is expressed at low or undetectable levels in hematopoietic cells but we find it to be highly expressed in FLS. The extracellular domain of PTPRS binds to proteoglycans in the extracellular matrix and binding to different proteoglycans results in differences in the intracellular functions of the phosphatase. This PTPRS-mediated mechanism of regulation of intracellular signaling by the extracellular matrix is called the proteoglycan switch. We find that the proteoglycan switch regulates in a PTPRS-dependent way the adhesion and invasiveness of FLS. We also find that interfering with the proteoglycan switch in vivo leads to decreased severity of arthritis in a mouse model. Our working hypothesis is that PTPRS is a key regulator of RA FLS destructive behavior. The objectives of this project are to establish PTPRS as a key regulator of extracellular matrix-induced signals in FLS and provide proof of principle that the proteoglycan switch is a drug target for RA.
In Aim 1 we will clarify whether PTPRS and the proteoglycan switch affect various aspects of FLS pathophysiology that are relevant to the pathogenesis of RA In Aim 2 we will identify the substrate of PTPRS that is affected by engagement of the proteoglycan switch and look into the signaling pathways controlled by PTPRS in a proteoglycan-dependent way In Aim 3 we will provide proof of principle that targeting PTPRS helps control RA activity in vivo and can be used as a combination therapy with anti-TNF therapy. The results of this project will shed light on the relationship between extracellular matrix composition and intracellular signaling in FLS. The disease-relevant long-term goal is to validate a novel approach to FLS targeted combination therapy for RA.

Public Health Relevance

We found that a protein belonging to a novel and currently untapped class of drug targets is present at high levels in cells lining the joints of RA patients, where we believe it promotes the aggressive behavior of these cells in joint inflammation and destruction. The objective of this project is to understand the role of this protein in RA. The lon-term goal is to design novel therapeutics against this protein to help control RA in patients non-responsive to current therapies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California, San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Mustelin, Tomas; Bottini, Nunzio; Stanford, Stephanie M (2018) The contribution of PTPN22 to rheumatological disease. Arthritis Rheumatol :
Zhao, Meng; Svensson, Mattias N D; Venken, Koen et al. (2018) Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70. Nat Commun 9:2627
Stanford, Stephanie M; Bottini, Nunzio (2017) Targeting Tyrosine Phosphatases: Time to End the Stigma. Trends Pharmacol Sci 38:524-540
Maeshima, Keisuke; Stanford, Stephanie M; Hammaker, Deepa et al. (2016) Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight 1:
Doody, Karen M; Bottini, Nunzio (2016) Chondrocyte clocks make cartilage time-sensitive material. J Clin Invest 126:38-9
Stanford, Stephanie M; Svensson, Mattias N D; Sacchetti, Cristiano et al. (2016) Receptor Protein Tyrosine Phosphatase ?-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice. Arthritis Rheumatol 68:359-69
Doody, Karen M; Stanford, Stephanie M; Sacchetti, Cristiano et al. (2015) Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Sci Transl Med 7:288ra76