Scientists at Penn State College of Medicine have found that the antidepressant paroxetine can halt the progression of osteoarthritis (OA), and regenerate damaged cartilage in the joints of mice. The team’s study found that paroxetine inhibited GRK2, an enzyme found at high levels in both human tissue and mouse models of the disease, and which acts to promote cartilage damage. Using paroxetine to inhibit GRK2 slowed the development of osteoarthritis in mice, and promoted cartilage healing in damaged joints.
The findings suggest paroxetine could represent the first-ever disease-modifying treatment for osteoarthritis, and also indicate that other compounds that counteract abnormal activity in cartilage-maintaining cells could be repurposed into therapies for the disease. “Our findings present elevated GRK2 signaling in chondrocytes as a driver of chondrocyte hypertrophy and cartilage degradation and identify paroxetine as a disease-modifying drug for OA treatment,” said study lead Fadia Kamal, PhD, assistant professor of orthopedics and rehabilitation. “This is important given that around 80% of the U.S. population will develop radiographic evidence of osteoarthritis by age 65 and with the growing prevalence of osteoarthritis risk factors, such as obesity and diabetes, osteoarthritis will likely carry an even greater burden in the future.”
The researchers report on their results in Science Translational Medicine, in a paper titled, “Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis.”
Osteoarthritis is a disease of the joints that is characterized by progressive cartilage degeneration, the authors explained. The disorder affects more than 30 million adults in the U.S., where it represents the fifth-leading cause of disability. The team cites figures indicating that osteoarthritis was responsible for $305 million in U.S. healthcare costs in 2013, equivalent to approximately 1% of the country’s gross domestic product.
While some treatments can relieve the symptoms of osteoarthritis, there are currently no therapies that alter or reverse the core mechanisms that damage cartilage in patients. “With no disease-modifying treatment available and with the growing prevalence of OA risk factors within the U.S. population, OA will carry an even greater burden in the future,” the authors stated. “Therefore, there is a dire need to identify therapeutic targets, approaches, and/or agents that can actively halt or reverse the OA disease process.”
Kamal further explained, “Osteoarthritis destroys joint cartilage and results in pain and disability. Patients live with this pain until their cartilage is extremely degenerated. Unfortunately, an invasive artificial joint replacement surgery is the only treatment orthopedists are currently able to offer. There has been a dire need to identify novel therapeutic targets, approaches or agents that can actively halt or reverse the osteoarthritis disease process.”
In previous research, Kamal and her colleagues had found that elevated expression and activity of the enzyme G protein-coupled receptor kinase 2 (GRK2) leads to pathologic cell growth in heart and kidney disease. She explained that osteoarthritis is similarly driven by pathological growth of cartilage cells, a process called chondrocyte hypertrophy, but how this proliferation occurs had been a mystery.
With this knowledge of the role of GRK2 in heart and kidney disease, Kamal and her team investigated the enzyme in osteoarthritis patients. While studying samples of human cartilage, they observed that samples from patients with osteoarthritis harbored much higher levels of GRK2.
The team confirmed that mice with osteoarthritis also showed high levels of GRK2, which damaged cartilage by causing cartilage cells to release more cartilage-degrading enzymes. “We discovered a central role for GRK2 in cartilage degeneration, where GRK2 pushes chondrocytes to destroy the cartilage matrix surrounding them instead of replenishing and maintaining it.” said Kamal. “In other words, the cells receive a bad signal to destroy cartilage.”
The researchers confirmed the role of GRK2 in cartilage degeneration through two sets of experiments in mice. They showed that deleting the gene that encodes GRK2 slowed the development of osteoarthritis in engineered mice. And in mice with surgically induced osteoarthritis, treatment using the GRK2 inhibitor, paroxetine, had similar effects. “Paroxetine is an SSRI and a potent GRK2 inhibitor with higher selectivity for GRK2 over other GRKs,” they pointed out.
In both cases, they found that not only did GRK2 deletion/inhibition prevent chondrocyte hypertrophy and halt osteoarthritis progression, but it also promoted cartilage regeneration. “We found that paroxetine could return cartilage cells back to a normal state and preserve the cartilage surface,” said Kamal.
In vitro studies in cultured human osteoarthritic cartilage obtained from patients undergoing knee replacement surgery also demonstrated the ability of paroxetine to mitigate chondrocyte hypertrophy and cartilage degradation.
“Here, we demonstrate that the clinically used antidepressant paroxetine is a disease-modifying agent in OA that prevents cartilage degeneration and promotes matrix regeneration,” the investigators stated. They are currently seeking FDA approval to start a trial evaluating paroxetine as a treatment for osteoarthritis. “As a clinically used antidepressant with known pharmacological and toxicological profiles, paroxetine represents a promising therapy for OA that can be easily translated from bench to bedside,” the team noted. Kamal added, “If this trial works, we will have found a new solution to an age-old problem of joints in the body wearing out because of cartilage destruction and loss. We hope to intervene with this disease-modifying treatment for the benefit of our patients.”
