More than 40% of individuals will develop osteoarthritis (OA) during their lifetime. Hand osteoarthritis is a common and debilitating medical condition that affects mainly women, especially around the time of the menopause. 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. Currently clinicians have no effective treatments that modify their disease. A new study, published by researchers at the University of Oxford has identified that Talarozole, a drug that is known to increase retinoic acid, was able to prevent osteoarthritis in disease models. This drug has been originally developed to treat acnes, psoriasis and other skin conditions; yet, time ago its development was disconitnued for this purpose. It works as an inhibitor of the metabolism of retinoic acid by blocking CYP450 hydroxylases (CYP26A1/B1) that inactivate retinoic acid. Because of this mechanism, it is called a retinoic acid metabolism blocking agent (RAMBA).
Retinoic acid is an actie bioagent able to induce cellular committment and differentiation (specialization) in many cellular types and even in cancer cells. Anomalies of cell differentiation are reported in cartilage during degenerative conditions like rheumatoid arthritis, juvenile arthritis and also common hand/knee osteoarthritis. To avoid the cartilage cell (chondrocytes) loss, retinoic acid may help to “reactive cells” aring from the damage to rebuild cartilage at least partially. Yet, retinoic acid alone is difficult to be handled freely since it may induce even serious side effects, as seen in dermatology, oncology and rheumatology appplications. Therefore indirect way are preferred to handle this endogenous substance to enhance its biological effects. Talarozole has the ability to be extremely selective on CYP26 enzymes (300-fold selectivity over CYP17 and CYP19A or estrogen aromatase). In this research, scientists started by investigating a common gene variant that had been linked to severe hand OA.
Using patient samples collected at the time of routine hand surgery, as well as a number of experimental models, they were able to identify retinoic acid as a key molecule that was especially low in ‘at risk’ individuals. 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. Dr Neha Issar-Brown, Director of Research and Health Intelligence at the charity Versus Arthritis, said: “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 research is still at an early stage, but 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.
Knee osteoarthritis is nonetheless invalidating that hand OA. Researchers of may institutions have noted that women with knee osteoarthritis report more pain than men, but the reason for this difference has been unclear. Now, investigators at Hospital for Special Surgery (HSS) have discovered that at the time of total knee replacement, women have significantly increased levels of immune cells called mast cells in synovial tissue surrounding the knee joint than men. Their findings, presented already at the Annual Meeting of the American College of Rheumatology 2022 last November, may help future research explore why women with knee osteoarthritis report worse pain than men. Synovial tissue lines the knee joint and produces fluid that helps the joint move. It can become inflamed as osteoarthritis progresses. Pathologists at HSS have been generating data on different types of cells found in synovial tissue, including mast cells, which are commonly known for producing histamine during allergic reactions and asthma.
Basic research by other scientists has suggested a link between mast cells and osteoarthritis progression and pain. Dr. Orange and his tam studied joint tissue obtained from 96 women and 61 men who underwent total knee replacement at HSS. They counted the number of cells for more than a dozen cell types typically found in synovial tissue and examined synovial fluid and blood using a high-powered microscope. They also evaluated patient-reported pain outcomes collected with two validated surveys. The investigators discovered that synovial tissue from women had significantly more mast cells, averagely 63 per sample area, compared to 46 in tissue from men. They also found higher levels of a enzyme of mast cells called tryptase in synovial tissue from women than men, providing further evidence of increased mast cell activity. No other differences in synovial tissue between sexes were observed. Finally, as expected, women reported worse pain than men on both surveys.
Tryptase is the most abundant secretory granule-derived serine proteinase contained in mast cells and has been used as a marker for mast cell activation. Tryptase is involved with allergenic response and is thought to act as a mitogen for fibroblasts. Its biological action could explain the bronchial thickening in chronic asthma, the proliferation of fibroblasts in areas of chronic inflammation, e.g. the induration or sclerosis of the skin areas affected by chronic dermatitis and other allergic manifestations. Tryptase is currently the main mast cell biomarker available in medical practice. Tryptase determination is a quantitative test performed in serum or plasma for the diagnosis, stratification, and follow-up of mast cell-related conditions. Because mast cells are tissue-resident cells, the detection of an acute tryptase release in the bloodstream is protracted, with a delay of 15 to 20 minutes after the onset of symptoms and a peak at approximately 1 hour. Longer blood tryptase levels could be taken as a “clinically sure” inflammatory attack in the knee.
This enzyme coud become a monitoring marker for knee osteoarthitis in women, shaping therefore a new type of rheumatologic “personalized” clinical diagnosis. Dana Orange, MD, rheumatologist, assistant professor at The Rockefeller University and senior author of the study, concluded this way: “Others have speculated that women tend to delay surgery more than men, but when we looked in our database, that wasn’t true. We studied synovial tissue removed at the time of total knee arthroplasty to look for a biological reason that may explain the difference in reported pain between sexes. We hope our findings encourage other researchers to start thinking about biological factors that may contribute to sex differences in patient-reported pain in knee osteoarthritis”.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemsitry.
Advised in this website
Clin Immunol. 2022 Nov; 244:109117.
Front Immunol. 2022 Jun; 13:871008.
J Exp Orthop. 2022 Jan 25; 9(1):13.
Diab Metab Syndr Obes. 2020; 13:1491-1497.
Dott. Gianfrancesco Cormaci
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