- Osteoarthritis is a leading cause of disability worldwide — a debilitating disease that limits movement and causes pain in the joints of the knees, hips, and hands.
- Hand osteoarthritis affects millions of people and is much more common in women than in men.
- New research has proposed mechanoinflammation as the primary driver of hand osteoarthritis and identified the importance of retinoic acid in its development.
- The research team showed the drug talarozole boosts the levels of retinoic acid in the joint, suppressing mechanoinflammation — potentially modifying the course of the disease.
Osteoarthritis(OA) is a degenerative disease of the joints that commonly affects the knees, hips, and hands. It is a chronic condition that affects over
The cause of OA is not entirely understood, but it happens when cartilage — the smooth, slippery, cushioned surface covering the ends of bones — breaks down and becomes thin and rough.
Loss and damage to the cartilage stop the bones in the joint from freely moving, causing pain and swelling as the body tries to heal the tissue. In people with OA, the healing process causes more changes to the underlying bone that can exacerbate symptoms — pain, swelling, stiffness, and reduced flexibility.
“[…] Despite often being dismissed as just a few aches and pains, OA can have a profound and far-reaching impact on life, affecting people’s ability to work, care for a family, or live independently,” said Dr. Neha Issar-Brown, Director of Research and Health Intelligence at Versus Arthritis, which funded the research, in a press release.
There is no cure for OA, and the symptoms can worsen over time. Treatments for the disease focus on pain and swelling management – to help people with the disease keep mobile and active.
- living an active and healthy lifestyle
- taking pain medication
- physical therapies to strengthen the muscles around the joints
New research led by Dr. Tonia Vincent, professor of musculoskeletal biology and director of the Center for Osteoarthritis Pathogenesis at the University of Oxford, has identified a cellular pathway involved in the disease. In addition, the research has shown that the drug talarozole can target this pathway, possibly changing the progression of OA.
The research is published in the journal Science Translational Medicine.
Previous research has investigated the retinoic acid metabolism-blocking (RAMBA) drug talarozole as a treatment for skin disorders primarily due to its ability to reduce the breakdown of retinoic acid.
Retinoic acid, a metabolite of vitamin A is known to be involved in cellular communication and the
Dr. Vincent explained to Medical News Today that this new study “showed that the variant in the gene meant that these individuals had very low levels of retinoic acid to start with (and presumably drop even lower when the joint is injured). This was associated with higher inflammation in the tissue.”
The multidisciplinary research team involved hand surgeons, geneticists, data scientists, and biologists to study the biological significance of the relationship between the gene variant and severe OA. The scientists used data from the UK biobank study, combined with 33 samples of Articular cartilage taken from people with hand OA during routine surgery.
RNA sequencing of the tissue showed a link between the ALDH1A2 gene and inflammatory genes, leading the team to identify mechanoinflammation as one of the primary causes of OA in the patients studied.
“We showed that the variant in the gene meant that these individuals had very low levels of retinoic acid to start with (and presumably drop even lower when the joint is injured). This was associated with higher inflammation in the tissue.”
The team also identified a link between cartilage injury and a reduced expression of ALDH1A2.
The effect of talarozole as a retinoic acid metabolism blocking agent (RAMBA) was studied using in vivo and ex vivo animal models.
The research team demonstrated that talarozole stopped the reduction in the expression of the retinoic acid-producing genes, and an increase of retinoic acid in the joints was linked to the drug.
The researchers also observed a reduction in inflammation and cartilage injury — noting a reduction in mechanoinflammatory gene expression within six hours after surgery, stopping further cartilage and joint damage.
Dr. Vincent told MNT that the most exciting part of this research is the “identification of a completely new targetable pathway that was identified through a human genetic study and the fact that there are already drugs that have been tested for other indications that could be ‘repurposed’ to treat patients with OA”.
Dr. Issar-Brown echoed these thoughts:
“There is an urgent need for disease-modifying treatments designed to prevent or reverse the painful symptoms of OA. This study reveals a new understanding of the causes of hand osteoarthritis, which could lead to identifying new biological targets for intervention in hand OA.”
This multidisciplinary approach shows talarozole can boost retinoic acid levels and reduce mechanoinflammation in the joint. Combining this with the acceptable safety profile of the drug in human subjects means the next step is a clinical study to see if it can work as a disease-modifying treatment in patients.
Dr. Vincent noted that recruitment for the clinical trial begins in January 2023, with results expected in 2024.