U50 488H KOR agonist reduces cartilage degradation, chondrocyte hypertrophy and bone loss in osteoarthritis

Shradha Sinha; Anirban Sardar; Shikha Verma; Geeta Dhaniya; Ritu Trivedi

doi:10.1016/j.intimp.2025.115150

U50 488H KOR agonist reduces cartilage degradation, chondrocyte hypertrophy and bone loss in osteoarthritis

Int Immunopharmacol. 2025 Jul 8:162:115150. doi: 10.1016/j.intimp.2025.115150. Online ahead of print.

Authors

Shradha Sinha¹, Anirban Sardar¹, Shikha Verma¹, Geeta Dhaniya², Ritu Trivedi³

Affiliations

¹ Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
² Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
³ Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: ritu_trivedi@cdri.res.in.

PMID: 40633208
DOI: 10.1016/j.intimp.2025.115150

Abstract

Osteoarthritis is a chronic joint disease-causing significant pain and discomfort especially in the aging population. It is characterized by inflammation, extracellular matrix degradation, chondrocyte apoptosis, hypertrophy and subchondral bone degeneration. In this study, we explored the disease modifying activity of Kappa Opioid Receptor (KOR) agonist U50 488H in in-vitro and in-vivo model of osteoarthritis. U50 488H reduced the production of pro-inflammatory cytokines, lowered reactive oxygen species (ROS) generation and inhibited the expression of hypertrophic and catabolic factors induced by IL-1β in rat articular chondrocytes. Additionally, the intra articular injection of U50 488H slowed the progression of osteoarthritis in anterior cruciate ligament transected (ACLT) rat model. Histological findings revealed that U50 488H preserved the proteoglycan content, cartilage thickness and cartilage integrity. Furthermore, subchondral bone analysis by micro-CT demonstrated that KOR agonist protected the bone microarchitecture. In conclusion, these findings suggest that KOR signalling has both chondroprotective and osteoprotective effects in osteoarthritic condition.

Keywords: Chondrocytes; IL-1β; Inflammation; KOR; Osteoarthritis; Subchondral bone.