Extracellular matrix and proteolysis: mechanisms driving irreversible changes and shaping cell behavior

The extracellular matrix (ECM) provides structural support and dynamic signaling cues, governing cellular behavior and tissue integrity. ECM remodeling, critically regulated by irreversible proteolysis, profoundly impacts development, homeostasis, and disease. This review examines the major families of ECM-degrading proteases-matrix metalloproteinases (MMPs), serine proteases, a disintegrin and metalloproteinases (ADAMs), metalloproteinase with thrombospondin motifs (ADAMTSs), and cysteine proteases-emphasizing their shared regulatory mechanisms and proteolytic activity in reshaping the tissue microenvironment. These proteases exhibit functional redundancy, particularly in the generation of matrikines, growth factors, and cytokines from common ECM substrates, all contributing to ECM softening. These overlaps in substrates and the resulting bioactive molecules amplify proteolysis within the tissue. The generated matrikines, growth factors, and cytokines further drive ECM remodeling through feedback loops, influencing the expression and activation of proteolytic enzymes. Despite these shared mechanisms, protease families demonstrate cell-specific functional specialization shaped by transcriptional programs, microenvironmental signals, and subcellular targeting, ensuring precise spatiotemporal proteolysis during processes such as development, wound healing, and immune responses. Dysregulation of this intricate proteolytic network contributes to chronic pathologies and cancer. Thus, understanding and targeting these processes is crucial for therapeutic intervention and the improved regulation of biological functions. Collectively, these insights reveal how irreversible ECM proteolysis orchestrates complex, context-dependent biological responses in both health and disease.