Potential disease-modifying drug for osteoarthritis identified

by Tom O'Connor, UNMC public relations | May 15, 2019

Image with caption: From left, Anna Spagnoli, M.D., and Tieshi Li, Ph.D.

From left, Anna Spagnoli, M.D., and Tieshi Li, Ph.D.

Researchers have gained a better understanding of how osteoarthritis (OA) occurs and have identified a potential new drug that could be used to treat OA, a debilitating disease expected to affect 67 million people in the United States by 2030.

The research is detailed in the May 8 issue of "Science Translational Medicine."

The collaborative research project involved scientists at four U.S. institutions -- UNMC, Rush University Medical Center, University of North Carolina at Chapel Hill and Duke University -- as well as Tongji Medical College in China and Gulhane Military Medical School in Turkey.

The lead author on the study is Tieshi Li, Ph.D., assistant professor, pediatrics, at UNMC. The senior author on the study is Anna Spagnoli, M.D., chair of the UNMC Department of Pediatrics and director of the Child Health Research Institute, pediatrician-in-chief and senior vice president for Children's Hospital & Medical Center.

Dr. Spagnoli joined UNMC and Children's earlier this year after working previously at Rush University Medical Center and the University of North Carolina at Chapel Hill. Dr. Li worked with Dr. Spagnoli at Rush University Medical Center and joined her team in Omaha.

Using several animal models and human samples from people with osteoarthritic joints, the researchers determined that the TGF-beta type II signaling receptor (TGFBR2) regulates joint development during fetal life as well as joint maintenance through the lifespan. It does this by modulating key components of a family of inflammatory cytokines called the IL-36 system.

Researchers discovered that if subjects lacked TGFBR2 that it led to OA and impaired movements. In aging mice that naturally develop OA and in mice with post-traumatic OA, researchers found a profound decrease in TGFBR2.

In human joints, the study found that the decrease in TGFBR2 correlated with the severity of the OA. They also found that the decrease in TGFBR2 was associated with an increase of IL-36-alpha and a decrease in its antagonist (IL-36 receptor antagonist) in humans and all four animal models studied.

These findings indicated that TGFBR2 is a potential target for treating OA. Researchers then focused on the IL-36 system as a novel and critical downstream mediator of TGFBR2 and a potential target to treat OA.

With most of the experiments performed by Dr. Li, the IL-36 receptor antagonist was injected in knee joints affected by OA -- and in the key finding of the study -- it was found that the injection improved the OA in mice and in human cartilage cells from people with OA and decreased metalloproteinases, enzymes that destroy joint cartilage.

"This is truly a significant breakthrough," Dr. Spagnoli said. "Currently, we are lacking any drugs that are capable of preventing, treating or halting the progression of OA, and the ultimate treatment is surgical joint replacement. Further studies need to be done, but we are excited by the positive response seen with the injection of the IL-36 receptor antagonist. It should provide hope to OA sufferers."

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jason
June 10, 2019 at 4:52 PM

Only trouble take ten years to appear if we are lucky to pass phase 3.If any good probably be exspensive or will go under ground never to be heard again.Sorry for negtive response just read that many articles regarding OA and we are no where near drug which would help us with our disease we are exaclty where was century ago, disease to complex till we know which gene`s to switch off.

Nicholas Heimann
May 17, 2019 at 9:40 AM

Good, OA is definitely related to inflammation, however, simply shutting down cartilage degrading pathways is a half measure. Healthy joints rely upon a balance of constant degradation and rebuilding of the cartilage. The IL-36 receptor antagonist could be used in conjunction with the appropriate nutrients and agents that help in the deposition of healthy cartilage ECM to repair the system, however, overuse could lead to cartilage structural deformations.

Kari Simonsen
May 15, 2019 at 8:50 PM

Congratulations, Drs. Li and Spagnoli and to the entire research team!

Teri Mauch
May 15, 2019 at 7:58 PM

Very exciting! Congratulations!

Myrna McColley
May 15, 2019 at 9:56 AM

There is hope for us all!

Patricia Anderson
May 15, 2019 at 8:37 AM

Congratulations, Drs. Li and Spagnoli! Great work.