A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification
Mauricio N. Ferrao Blanco, R Lesage, Nicole Kops, Niamh Fahy, Fjodor Bekedam, Athina Chavli, Y.M. Bastiaansen-Jenniskens, Liesbet Geris, M.G. Chambers, Andrew A. Pitsillides, Roberto Narcisi, Gerjo J.V.M. van Osch
Abstract
activation of EPHA2 in healthy chondrocytes increases inflammatory mediators and induces hypertrophic differentiation, a hallmark of endochondral ossification. We then evaluated the effect of EPHA2 inhibition using the tyrosine kinase inhibitor ALW-II-41-27 in cultured human chondrocytes from individuals with osteoarthritis, demonstrating significant reductions in both inflammation and hypertrophy. Additionally, systemic subcutaneous administration of ALW-II-41-27 in a mouse osteoarthritic model attenuated joint degeneration by reducing local inflammation and pathological endochondral ossification. Collectively, this study demonstrates a novel drug discovery pipeline that integrates computational, experimental, and animal models, paving the way for the development of disease-modifying treatments for osteoarthritis.