Matrix metalloproteinases and their inhibitors in connective tissue remodeling

Abstract

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.

Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise

“…MMPs 1 and 13 were selected as they are known to be active against fibrillar collagens, including the predominant collagen type I 1, 28, 29, 30. MMP‐3 was selected as it degrades other minor proteins in tendon matrix, including collagens III, IV, IX, and X, and also proteoglycans and elastin 28, 29, 30, 31, 32, 33. The C1,2C (or COL 2 3/4C short) antibody detects the carboxy terminus of fragmented type I and II collagen, cleaved by collagenases MMP‐1, MMP‐8 or MMP‐13 21, 34, 35, 36, 37…”

A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

“…Enzymes of this family, such as tissue collagenase (MMP-1), stromelysin-1 (MMP-3), type IV collagenase (or gelatinase A, MMP-2) and gelatinase B (MMP-9) are secreted as zymogens, and once activated, they are able to remove connective tissue during normal turnover and pathologic breakdown [5]. The latent form (proenzyme) can be activated, at least "in vitro", by other proteases (e.g., plasmin, plasma kallikrein, tissue plasminogen activator, which are present in the inflammatory micro-environment), as well as by mercurials (e.g., 4-aminophenylmercuric acetate) [6].…”

Immunopurification and characterization of a collagenase/gelatinase domain issued from basement membrane fibronectin

“…To date, it seems that tissue remodeling in both normal and pathological states is dependent on matrix metalloproteinase (MMP) activities. On the other hand, some MMPs such as the 92 and 72 kDa collagenases were found to be structurally related to fibronectin [10,15]. In the present work, we have shown that after limited digestion of an intact basement membrane, collagenase/gelatinase activities are expressed.…”