Therapeutic potential of dehydroepiandrosterone in early osteoarthritis: Modulating cartilage ECM stiffness through...

Osteoarthritis (OA) is characterized by progressive cartilage degeneration and extracellular matrix (ECM) stiffening, yet effective disease-modifying therapies remain limited. This study evaluated the chondroprotective effect of dehydroepiandrosterone (DHEA) in early OA and elucidated its underlying mechanisms. Using rabbit and mouse models, we demonstrated that intra-articular DHEA administration attenuated cartilage damage, reduced catabolic enzyme expression, and preserved ECM elasticity. Mechanistically, DHEA downregulated lysyl oxidase (LOX), suppressed activation of the RhoA/ROCK/MLC signaling cascade, and thereby mitigated ECM stiffening. The protective effects were partly dependent on LOX inhibition, suggesting a dual regulatory mechanism. These findings identify DHEA as a potential disease-modifying agent that targets LOX-RhoA/ROCK/MLC signaling to maintain cartilage homeostasis in early OA, warranting further clinical investigation.