Pharmacologic inhibition of EPHA2 decreases inflammation and pathological endochondral ossification in osteoarthritis

Abstract

AbstractLow-grade inflammation and pathological endochondral ossification are processes that underlie the progression of osteoarthritis. In this study, data mining on publicly available transcriptomic datasets revealed EPHA2 to be associated both with inflammation and endochondral ossification in osteoarthritis. EPHA2 was further investigated using a computational model of cellular signaling networks in chondrocytes. In silico activation of EPHA2 increased inflammatory mediators and triggered the hypertrophic differentiation of healthy chondrocytes, the phenotypic switch characteristic of endochondral ossification. Inhibition of EPHA2 in cultured chondrocytes isolated from individuals with osteoarthritis reduced inflammation and hypertrophy. Systemic subcutaneous administration of the EPHA2 inhibitor ALW-II-41-27 attenuated joint degeneration in a mouse model, attenuating local inflammation and pathological endochondral ossification. Collectively, we demonstrate that pharmacological inhibition of EPHA2 with ALW-II-41-27 is a promising disease-modifying treatment that paves the route for a novel drug discovery pipeline for osteoarthritis.