Research Summary: U50 488H, a KOR agonist, reduces chondrocyte hypertrophy, inflammation, cartilage degradation and subchondral bone loss, preserving cartilage integrity and bone structure, suggesting its dual role in osteoarthritis treatment.
Author interview
Mrs. Shradha Sinha graduated in 2016 and completed her Masters degree in Zoology from University of Lucknow in 2018. She qualified CSIR-NET JRF and joined CSIR-CDRI in 2018 as a Junior Research Fellow for pursuing research under the supervision of Dr. Ritu Trivedi, Senior Principal Scientist, Head, Department of Endocrinology. Currently she is working as a Senior Research Fellow under Dr. Ritu’s guidance. Her research mainly focuses on bone and cartilage health. She is exploring novel targets and therapeutics for the treatment of bone and cartilage related disorders like osteoporosis and osteoarthritis.
Lab: Dr. Ritu Trivedi, Central Drug Research Institute, Lucknow
What was the core problem you aimed to solve with this research?
Osteoarthritis is one of the most degenerative diseases that imposes heavy burden on the global healthcare. The disease impairs load bearing joints like hip and knee joints affecting the day-to-day activities of patients. Treatment strategies include NSAIDS in the early stage and joint replacement in the last stage of osteoarthritis. But these interventions focus mainly on alleviating the symptoms rather than eliminating the root cause of the disease. Moreover, these therapies are concomitant with various side- effects. Intra-articular injection of U50 488H, KOR agonist targeted the chondrocyte dysfunction as well as the subchondral bone deterioration. Thus, preventing the cause and effect of the disease.
How did you go about solving this problem?
We utilized both in-vitro and in-vivo methods to establish the therapeutic role of KOR agonist in osteoarthritis. Anterior cruciate ligament transection surgery was performed in female Sprague Dawley rats as it mimics the human osteoarthritic pathophysiology very closely. For the treatment, KOR agonist U50 488H was injected in the affected joints for 6 weeks after which the joints were harvested and analysis was done. In order to elucidate the mechanism of action of KOR agonist, chondrocytes were treated with U50 488H and key mediators of cartilage metabolism were assessed.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Bone related disorders like osteoporosis and osteoarthritis are one of the major health implications in the aging population especially women in their post-menopausal ages. Patients with osteoarthritis have compromised locomotion and mobility thus imposing the urgent need to effectively manage the disease. Current interventions help in mitigating symptoms like inflammation, pain and swelling but are bestowed with numerous side effects. Opioids when taken orally reduce pain but cause sedation and other neurological disturbances. We performed the localized administration of Kappa Opioid Receptor Agonist U50 488H to maximize its therapeutic potential with simultaneous minimization of its side effects. And as hypothesized we observed the improvement in the osteoarthritic pathophysiology by reducing the pain as well as healing the complete osteochondral unit i.e. cartilage and bone.
Potential molecular mechanism involved in U50 488H treatment in chondrocytes subjected to IL1-β. U50 488H KOR agonist mitigated ECM degradation, inflammation and chondrocyte hypertrophy via suppression of NF-Kb/ HIF-2α activation.
What are the potential implications of your findings for the field and society?
Our findings indicate the application of local injection of KOR agonist in treatment of osteoarthritis. This treatment strategy is effective in managing the symptoms along with preventing the further degradation of cartilage and bone which is the root cause of the disease. Thus, having dual targets without its associated side effects.
These findings would be helpful in uncovering new mechanisms focusing on the osteochondral unit. Moreover, this research contributes to precision and the future of osteoarthritis treatment.
What was the exciting moment during your research?
For mimicking the human osteoarthritic conditions, ACLT (anterior cruciate ligament transection) was performed in the rat knees. KOR agonist U50 488H was intra-articularly injected for 6 weeks. After which the beneficial effects of KOR agonist were assessed in the cartilage as well as the subchondral bone regions. As this was a non-conventional method of drug delivery, we were apprehensive of the results. But the positive results in both cartilage and underlying subchondral bone elated us. We did extensive histological analysis for the cartilage region while for the bone we performed micro-CT. And to our pleasant surprise the KOR agonist not only protected the cartilage from exacerbated damage due to ACLT but also exerted its osteoprotective effects on the subchondral bone. The effects were not just restricted to the morphological parameters; these were also reproduced at the molecular level.
Paper reference https://www.sciencedirect.com/science/article/abs/pii/S1567576925011403
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