Department of Orthopaedics Receives Two NIH Grants to Study Osteoarthritis of the Knee

Osteoarthritis (OA) causes an estimated 30 million-plus Americans to live with swollen joints, pain, limited mobility, and other adverse health effects. Unfortunately, there is no cure and no treatment yet shown to slow progression of this disease.

Along with colleagues from the Department of Orthopaedics and the John P. Hussman Institute of Human Genomics, Thomas Best, M.D., Ph.D., vice chair of research for orthopaedics at the University of Miami Miller School of Medicine, aims to change that.

Bolstered by two recent R21 grants from the National Institutes of Health (NIH), Dr. Best and colleagues will take a deeper dive into the role of inflammation in disease mechanisms through genetic and regenerative medicine approaches. One goal is to identify distinct “phenotypes” or subtypes of OA, develop targeted treatments for each, and determine how to prevent people from developing OA or progressing once diagnosed.

“We have traditionally thought of osteoarthritis as a degenerative disease. Cartilage is breaking down and bones spurs are getting in the joint space area, so that’s true,” said Dr. Best, who is also a professor of orthopaedics, family medicine, biomedical engineering, and kinesiology at the Miller School and research director at the University of Miami Sports Medicine Institute. “But to the point about different phenotypes, we also know that inflammation in many cases plays a far greater role than we ever thought in the progression of OA.”

Dr. Best and Anthony Griswold, Ph.D., associate director of the Center for Genome Technology at the Hussman Institute, are principal investigators for the research to evaluate OA phenotypes and disease progression using genomics techniques to analyze the miRNA expression within the synovial fluid.

Dimitrios Kouroupis, Ph.D., assistant professor of orthopaedics, will lead the other research project. The grant will allow investigators to evaluate the stem cells within the infrapatellar fat pad — a cushioning structure behind the kneecap — to see if the cells or their environment can be manipulated to treat OA.

Taking a New Approach to Research

There is no time to lose in OA research. The disease is “very common, very costly, and the incidence is rising,” Dr. Best said. It has been predicted that by 2030, OA will be the most common chronic disease worldwide.

OA can present differently in different people, a challenge that has impeded researchers in the past; and the condition often progresses or changes over time, further complicating efforts to develop effective treatments.

The investigators plan to study the Osteoarthritis Initiative (OAI), a large, longitudinal database of people with the condition. Next, they will look for genetic molecular information in extracellular RNA from 200 people to find genetic differences among these subtypes, with the goal of finding targeted therapies for individuals living with specific types of OA.

Investigating Immunity and Inflammation

The infrapatellar fat pad is the focus of the second NIH R21 grant. The pad is rich in stem cells and synovial fluid. The ways in which Dr. Best and colleagues plan to alter this environment involve mesenchymal stem cells, substances known as cytokines, and several factors driving changes in immunity and inflammation, including a neuropeptide known as “substance P” that is highlighted correlated with pain in many patients with OA.

The research team will look into ways to inhibit the activity of substance P and other factors driving inflammation, including cell-free, more stable alternatives to the stem cells. The discovery that mesenchymal stem cells are able to degrade substance P is so promising that it is protected by a patent issued to the University of Miami.

The NIH scored the two R21 grant proposals in the first and third percentile — extremely high rankings that validate their scientific potential.

“Obviously, we’re very excited, very pleased, and very appreciative of the NIH support. But most importantly I want to acknowledge my colleagues, Drs. Griswald and Kouroupis, who spearheaded these interdisciplinary grants,” Dr. Best said.

Future Directions

The researchers are developing a collaboration with the esteemed Stedman Philippon Research Institute in Vail, Colorado. Drs. Best, Griswold, and Kouroupis, Chair of Orthopaedics Francis Hornicek, and Lee Kaplan, M.D., MHCM, director of the Sports Medicine Institute and professor of orthopaedics and biomedical engineering, recently spoke at the Seventh Annual Vail Scientific Summit on Advances in Regenerative Medicine.

Dr. Best and colleagues also plan to use the findings from the OAI-based synovial fluid project to develop their own study. In conjunction with Dr. Jean Jose, professor of radiology, they are collecting synovial fluid samples from UHealth patients, to be analyzed at the Hussman Institute.

Other UHealth research co-investigators include Armando Mendez, Ph.D., research associate professor of medicine in the Division of Endocrinology, Diabetes, and Metabolism and director of the DRI’s biomarker and immunoassay core laboratory.

Tags: Center for Genome Technology, Department of Orthopaedics, Dr. Francis Hornicek, Dr. Lee Kaplan, Dr. Thomas Best, Hussman Institute for Human Genomics, Miller School of Medicine, NIH, osteoarthritis, Sports Medicine Institute