Hope for a potential new treatment for osteoarthritis (OA) of the hand is held out by new research from the University of Oxford. The authors of the study, published in Science Translational Medicine, said that although "more than 40% of individuals will develop OA during their lifetime", with hand OA an extremely common form, yet "there are currently no licensed disease-modifying treatments" that effectively relieve symptoms or stop deformity and stiffness of the joints in this "disabling condition".
Study lead Tonia Vincent, professor of musculoskeletal biology and honorary rheumatologist at Oxford's Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), explained: "Hand osteoarthritis is a common and debilitating medical condition that affects mainly women, especially around the time of the menopause. We currently have no effective treatments that modify their disease."
'Promising Therapeutic Strategy' Identified
The NDORMS team have been studying the genetics of cartilage damage and inflammation in patients with OA and now report their discovery that common polymorphic variants in ALDH1A2, a gene that encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Their latest research attempted to elucidate the biological significance of this association, and then undertook laboratory experiments that identified a "promising therapeutic strategy" that limited the pathological effects in animals.
First the team set out to confirm that ALDH1A2 risk variants were associated with hand OA. They examined articular cartilage taken from 33 individuals in the UK Biobank cohort who were undergoing routine hand OA surgery. After stratification by genotype, RNA sequencing was performed and a reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed.
'Mechanoflammation a Primary Driver of OA'
Articular cartilage injury up-regulated similar inflammatory genes by a process that the team had previously termed mechanoflammation, they said, which they believe "is a primary driver of OA". Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration.
So they used animal models to test the effects of talarozole, a retinoic acid metabolism blocking agent (RAMBA), and found that the drug reversed both responses to injury in mouse and pig joints. Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism.
The authors wrote: "Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization, and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo, and identifies RAMBAs as potential disease-modifying drugs for OA."
Currently No Cure for Joint Damage
Asked to comment by Medscape News UK, Dr Wendy Holden, medical advisor to Arthritis Action and honorary consultant rheumatologist at North Hampshire Hospitals NHS Foundation Trust, said: "Hand osteoarthritis is an extremely common condition and for some people, especially women, the condition can run in families and can be severe, causing significant joint pain, stiffness and swelling, leading to bony deformity and sometimes extreme difficulty using the hands. There is currently no cure for hand osteoarthritis and no way of preventing joint damage.
"Researchers at the University of Oxford have identified a gene linked to severe hand osteoarthritis which causes inflammation in joint cartilage that is thought to be the first step leading to joint damage in osteoarthritis. They have also found a drug called talarazole which can block the damaging inflammatory effects of the gene on joint cartilage.
"Research is at a very early stage, and benefits have so far only been seen in test-tube cartilage models and in mouse and pig models of arthritis, but researchers hope that this may eventually lead to possible new treatments which may also prevent joint damage and disability in humans with osteoarthritis."
Urgent Need for Disease-modifying Treatments
Dr Neha Issar-Brown, director of research and health intelligence for Versus Arthritis, the charity that funded the research, said: "Around 8.5 million people in the UK live with OA. 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.
"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."
She added that although the research was still at an early stage, "with these encouraging findings we are a big step closer in being able to develop a new class of disease-modifying drugs to treat osteoarthritis, prevent chronic pain, and enable people to live well with the condition".
Clinical Trials Underway
The authors concluded: "Together with the observation that talarozole is able to suppress disease severity in mice after induction of OA, these data identify a potential disease-modifying class of drugs for use in human disease." The team said that as talarozole has an acceptable safety profile in human subjects, "a small proof of concept clinical study is underway to see whether this drug might represent a new disease modifying treatment in patients".
Conflicts of interest:T.L.V. is the lead for STEpUP OA Consortium, which has received grant support (to the University of Oxford) from Pfizer, Novartis, Fidia, Biosplice, Galapagos, and UCB. F.E.W. received funding from Versus Arthritis (to the University of Oxford) to support the administration of the Musculoskeletal Research Advisory Group. F.E.W. received consulting fees from Pfizer (to F.E.W.) in 2020. All other authors declare that they have no competing interests.
