Collagenase: a key enzyme in collagen turnover

Abstract

The primary agents responsible for cartilage and bone destruction in joint diseases are active proteinases that degrade collagen and proteoglycan. All four main classes of proteolytic enzymes are involved in either the normal turnover of connective tissue or its pathological destruction. These proteinases are made by different cells found within the joints. Both extracellular and intracellular pathways exist and individual enzymes can be inhibited by specific proteinaceous inhibitors that block their activity. Recent research has implicated the matrix metalloproteinases (MMPs) in many of the processes involved in joint diseases. The metalloproteinases are capable of degrading all components of the extracellular matrix. This family of proteinases contains a group of at least three collagenases that are capable of degrading native fibrillar collagen. Collagen degradation within joint disease is recognized as the irreversible step in the destruction of cartilage that leads to a failure in joint function. The collagenases are the enzymes necessary to initiate collagen turnover in normal connective tissue turnover and in disease.

The collagenolytic action of MMP-1 is regulated by the interaction between the catalytic domain and the hinge region

“…Excessive degradation of type I collagen is associated with a variety of human diseases, such as arthritis, tumor metastasis, and atherosclerosis [22]. Collagenases (such as MMP-1, MMP-8, and MMP-13) are able to cleave fibrillar collagen I, leading to the formation of two fragments corresponding approximately to and fragments of the mature collagen molecule [31,45].…”

“…The triple helix is made of two a-1 chains and one a-2 chain, and this structural assembly is characterized by a typical dichroic signal, peaking at 224 nm [20], which decreases only upon gross unwinding. Since physiological collagenolysis is crucial for several biological processes, such as tissue repair and remodeling, angiogenesis, and wound healing [3,21], and collagenases are the main MMPs involved in collagen turnover and remodeling [22][23][24], a clarification of the mechanism of processing of the triple helix by collagenases is of the utmost importance. Structural data on fibrillar collagen I [25][26][27] indeed have shown that, on the basis of the available three-dimensional structures of collagenases [28,29], the triple-helical structural assembly does not allow collagen I to come into close contact with the catalytic site of collagenases.…”

Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion

“…The human MMP gene family contains 24 identified members in four major groups -the collagenases, gelatinases, stromelysins, and MT-MMPs (Shingleton et al, 1996). The collagenases (MMP-1, MMP-8, and MMP-13) cleave triple helical collagen into two fragments; gelatinases (MMP-2 and MMP-9) degrade denatured collagen; and stromelysins (MMP-3, MMP-7, MMP-10 and MMP-11) degrade a broad range of molecules, including aggrecan, fibronectin, laminin and procollagens.…”

Collagen Degradation in the Abdominal Aneurysm

“…Biomechanical studies invariably show that the mechanical stability of the arterial wall essentially relies on fibrillar collagens in media and adventitia. 4 -6 These structural collagens are highly resistant toward proteolytic degradation, and the only mammalian proteases that have been shown to cleave the native triple helical region of fibrillar collagen are the classic collagenases of the MMP family 7 [ie, MMP-1, -8, and -13 and the membrane type-1 MMP (MT-1 MMP or MMP-14 8 )], as well as selected members of the cysteine protease family (ie, cathepsin K, 9,10 L, 11 and possibly S 12 ).…”