Researchers found a new target to treat RA by preventing the activation of fibroblast-like synoviocytes (above). [Dr. Karen Doody and Dr. Bill Kiosses, La Jolla Institute of Allergy and Immunology]
Researchers found a new target to treat RA by preventing the activation of fibroblast-like synoviocytes (above). [Dr. Karen Doody and Dr. Bill Kiosses, La Jolla Institute of Allergy and Immunology]

Stiffness in the fingers and toes, swollen joints with pain that comes and goes, for many years these were often dismissed as signs of getting older. Now, we know that they could very well be the initial symptoms of rheumatoid arthritis (RA), as the disease affects an estimated 1.3 million American adults between the ages of 30-60. Moreover, RA does not limit its effects to just the joints as it can lead to increased risk of heart attack, stroke and infections.

RA in most cases can be controlled to some degree with current immunosuppressive therapies that reduce inflammation and ultimately help slow the progression of the disease. However, in many patients, damage within joints continues to progress even while they are undergoing drug therapy. Yet, researchers at the La Jolla Institute for Allergy and Immunology (LIAI), in collaboration with colleagues at the University of California, San Diego, believe they have identified a novel drug target that focuses on the cells that are directly responsible for cartilage damage in affected joints.    

“Unfortunately, for around 40 percent of patients, immune-targeted therapies are not sufficient to bring them into full remission,” says the study's lead author Nunzio Bottini, M.D. Ph.D., associate professor at LIAI and UCSD. “If we could add a drug that acts on a different target without increasing immune suppression it could be very valuable.”

The findings from this study were published recently in Science Translational Medicine through an article entitled “Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.”

During the inflammatory process associated with RA, a specific set of cells called fibroblast-like synoviocytes (FLS) become mobilized. Typically, FLS are relatively quiescent, but have an important role in providing the lubrication fluid within joint. Upon activation however, FLS will invade the surrounding cartilage and secrete enzymes that break down the tissues and bones of the joint.    

“Even if your inflammation is completely under control with the help of current therapies—and they are excellent—the damage to the skeletal structure is not necessarily arrested in the long term because synoviocytes continue to cause damage,” explained Dr. Bottini. “And although synoviocytes are considered the main effectors of cartilage damage in rheumatoid arthritis there's no therapy directed against them.”

Mobilization of FLS is controlled by a signal transduction cascade regulated by a key enzyme called receptor protein tyrosine phosphatase sigma (RPTPσ), which the researchers found to be highly expressed on the surface of FLS cells.

“RPTPσ acts like an inhibitory signal that is precoded on the surface of these cells,” explains Karen M. Doody, Ph.D, postdoctoral researcher in Dr. Bottini’s laboratory and first author and first author on the current study.  

Normally, RPTPσ remains inactive on the cell surface through an interaction with surface proteoglycans. Dr. Doody found that if RPTPσ is freed from the proteoglycans it can weaken the ability of FLS to aggressively invade the joints cartilage.  

“Being able to activate RPTPσ's activity gives us a specific tool with which to adjust the migration and aggressiveness of synoviocytes in rheumatoid arthritis,” said Dr. Doody.

The investigators created a molecular decoy, synthesizing a small piece of RPTPσ’s extracellular domain and flooding the proteoglycans with the molecule, which occupied the binding sites for RPTPσ, preventing it from being sequestered. Additionally, the researchers tested their assay on a preclinical model of RA and found that the phosphatase decoy was able to alleviate the disease symptoms.

“The ultimate goal is to use biologics that target synoviocytes in combination with treatments that suppress the immune system, such as methotrexate or anti-TNF, to address all three aspects of rheumatoid arthritis: swollen joints as a result of inflammation, cartilage damage and bone damage,” concluded Dr. Bottini.

 








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