MMPs

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that remodel the extracellular matrix (ECM). They are secreted by a variety of cell types, including fibroblasts, macrophages, and cancer cells, and some are anchored to the cell surface as membrane-type MMPs (MT-MMPs).

Most MMPs are synthesized as inactive zymogens (pro-MMPs) and require proteolytic removal of their N-terminal pro-domain to become catalytically active. Activation can be mediated by other proteases or by autocatalysis, and activity is tightly controlled by tissue inhibitors of metalloproteinases (TIMPs).

The catalytic domain contains a zinc-binding motif that coordinates a zinc ion essential for proteolysis; calcium ions stabilize structure. Substrate specificity varies, with collagenases (MMP-1, MMP-8, MMP-13) cleaving fibrillar collagens, gelatinases (MMP-2, MMP-9) degrading denatured collagens and gelatin, stromelysins (MMP-3, MMP-10) broad ECM components, and MT-MMPs such as MMP-14 cleaving pericellular substrates.

Functions include normal development, wound healing, embryogenesis, angiogenesis, and tissue remodeling. They also participate in immune cell migration and release of cytokines and growth factors from matrix reservoirs.

Dysregulation of MMP activity is associated with diseases such as cancer, where MMPs facilitate invasion and metastasis; inflammatory diseases like rheumatoid arthritis; osteoarthritis; fibrosis; and cardiovascular remodeling after injury. Therapeutic strategies include MMP inhibitors, though clinical use has been limited by side effects and lack of specificity.

Key members include MMP-2 and MMP-9 (gelatinases), MMP-1 and MMP-8 (collagenases), MMP-3 (stromelysin), and MT1-MMP (MMP-14), which plays a critical role in pericellular proteolysis and activation of other MMPs.