Enzymes. 2026;60:135-168. doi: 10.1016/bs.enz.2026.05.001. Epub 2026 May 25.
ABSTRACT
The extracellular matrix (ECM) is a dynamic structural network essential for cellular organization, continuously remodeled by proteases such as matrix metalloproteinases (MMPs). Under physiological conditions, these proteases are strictly controlled through gene transcription, zymogen activation, and endogenous tissue inhibitors of metalloproteinases (TIMPs). TIMPs are vital endogenous inhibitors that tightly regulate various metalloproteinases, including MMPs, ADAMs (a disintegrin and metalloproteinase), and ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) to maintain healthy tissue homeostasis. Disrupting this balance between metalloproteases and TIMPs triggers uncontrolled ECM turnover, changes in immune responses, activation of cell surface receptors that can drive pathological conditions such as fibrosis, cancer, autoimmune diseases, arthritis, cardiovascular diseases and many others. Since their initial discovery, four human TIMPs have been identified, each demonstrating unique biological roles and tissue distributions. TIMPs represent an evolutionarily ancient protein lineage found across bacteria, invertebrates, and vertebrates. Despite their critical role in maintaining human health, there is still a significant gap in our understanding of exactly how their dysregulation drives disease progression.
PMID:42772838 | DOI:10.1016/bs.enz.2026.05.001