Abstract

Osteoarthritis affects approximately half a billion people worldwide and creates a significant economic burden, accounting for up to 2.5% of the national gross domestic product. Despite extensive research, a disease-modifying osteoarthritis drug remains unavailable. 2-hydroxyisocaproic acid is a physiological substance and the 2-hydroxy analogue of the essential amino acid leucine. This study investigates the potential of 2-hydroxyisocaproic acid to down-regulate key proteases involved in articular cartilage degradation. Specifically, we explore the use of 2-hydroxyisocaproic acid to inhibit the activity of matrix metalloproteinase 13 and a disintegrin and metalloproteinase with thrombospondin motifs 5, aiming to reduce the degradation of type II collagen and aggrecan, respectively, in osteoarthritis. Our findings demonstrate that 2-hydroxyisocaproic acid modulates and reduces the activity of both matrix metalloproteinase 13 and a disintegrin and metalloproteinase with thrombospondin motifs 5. Notably, 2-hydroxyisocaproic acid’s reversible inhibition of these enzymes does not involve covalent bonding, positioning it as an enzyme modulator or down-regulator rather than a direct inhibitor.