Proteolysis at the extracellular matrix interface: Molecular architects and regulators in health and disease

The extracellular matrix (ECM) is a dynamic and multifaceted scaffold that orchestrates tissue architecture, signalling and cell behaviour in multicellular organisms. Its function arises from the interplay between composition, three-dimensional organisation and mechanics, together with the tightly regulated activity of proteolytic enzymes and cell surface receptors. Cluster of differentiation (CD) molecules function as regulators at the cell-matrix interface by directing adhesion, migration, immune surveillance and the localisation of proteases within pericellular niches. Cathepsins, along with matrix metalloproteinases, ADAM and ADAMTS sheddases, orchestrate ECM turnover, basement membrane and interstitial remodelling, and the generation of bioactive fragments that influence cell fate and signalling. Disruption of these networks shifts tissues towards fibrosis, defective development, chronic inflammation, vascular pathologies and cancer. This review integrates foundational principles with recent discoveries to map the molecular architects and regulators of the matrix in health and disease, emphasising how composition and mechanics interact with protease-driven turnover and receptor-mediated sensing. Finally, we outline emerging therapeutic strategies that restore matrix balance through targeted modulation of protease activity, engineering of ECM-mimetic scaffolds with programmable mechanics and degradability, and tuning of CD-mediated signalling to promote regeneration and resolution.