Proteases hydrolyze the amide bond of a polypeptide chain, which can influence protein synthesis and function. This activity has been predominantly observed in the post-translational processing of lysyl oxidase (LOX) and lysyl-oxidase-like (LOXL) family proteins, which are indispensable for the remodeling of the extracellular matrix (ECM). Of the four classes, metallo- and serine proteases are known to catalyze the hydrolysis of pro-LOX and pro-LOXL family proteins into their processed forms. These LOX family proteins play instrumental roles in ECM remodeling by oxidatively deaminating the lysine and 5-hydroxy lysine residues, primarily in collagens and elastin, thus facilitating the formation of lysyl-derived covalent crosslinking that stabilizes the extracellular matrix assembly. Previous studies have established the presence of different proteolytic sites and the corresponding proteases for different LOX family proteins. However, the underlying mechanism of this protease-mediated processing of the LOX family in fibrotic tissue remodeling has remained elusive. In this review, we summarize the critical role of ECM crosslinking reactions catalyzed by the LOX family and provide an overview of proteolytic sites and corresponding proteases in fibrosis. Moreover, we discuss the potential catalytic mechanisms of bone morphogenetic protein-1, a metalloprotease, and Factor Xa, a serine protease, on LOX and LOXL2, respectively.
Joshi et al. (2026) studied this question.