Stephen M Krane and Weiguang Zhao MMPs with Collagenase Activity

In the process of remodeling of bone and other connective tissues, components of the extracellular matrix (ECM) such as collagens and proteoglycans are degraded and removed and new components are synthesized and deposited. The extent and intensity of remodeling is regulated by specific cells in each tissue that respond to signals from other cells and the matrix itself.1 Three main classes of enzymes have been implicated in the degradation of collagen, the most abundant component of the ECM. The first includes members of the matrix metalloproteinase (MMP) family.1-7 The second includes lysosomal cysteine proteinases such as cathepsins B and L which cleave collagens in the telopeptide domain.8,9 Another cysteine proteinase is cathepsin K (also designated cathepsin OC2, X, O or O2 by various investigators) which is highly expressed in osteoclasts10,11 and is the site of mutations in human pycnodysostosis,12 a disorder characterized by osteosclerosis. The third class includes serine proteinases such as plasmin, generated through the plasminogen activator system.13,14 Plasmin and cathepsin B have been implicated in the activation of MMP zymogens.15,16 After activation, certain MMPs are capable of degrading different types of collagen substrates. It is likely that such MMPs have a role in the physiological resorption of collagen in the uterus, in embryonic development and postnatal remodeling and in pathological processes such as local invasion by malignant tumors, resorption of periodontal structures in periodontal disease or the destruction of joints in rheumatoid arthritis.17-19

The MMPs or matrixins are members of a large subfamily of proteinases that have many common structural features6(see chapter 1). There have been more than 20 different MMP gene products described, 15 of which have been described in humans. Included in the MMP subfamily2-7 are human genes that encode at least three collagenases, three stromelysins and several gelatinases among which are cell-bound forms with a transmembrane domain.20 Although there is considerable conservation of amino acid sequence motifs among the human MMPs, only the collagenases ("fibroblast" collagenase [MMP-1 or collagenase-1],"neu-trophil" [MMP-8 or collagenase-2] and the rodent-type interstitial collagenases21-23 which are homologous to human collagense-3 or MMP-13)24 can cleave native, undenatured, "interstitial" collagens (types I, II, III, X) within the triple helical domain at neutral pH. According to one report, the 72kDa gelatinase also has collagenolytic activity if purified free

Collagenases, edited by Warren Hoeffler. ©1999 R.G. Landes Company.

from the Tissue Inhibitor of Metallo Proteinases (TIMP) and by this criterion could also be considered as a collagenase.25 One of the transmembrane MMPs, MT1-MMP, when expressed as a soluble protein using a construct in which the transmembrane sequence was deleted also had collagenase activity.26 Nevertheless, only one interstitial collagenase has been identified so far in the mouse, the human collagenase-3 homologue.59

In native type I collagen, collagenase cleavage occurs between a Gly/Ile in the a1(I) chain and a Gly/Leu in the a2(I) chain, 3/4 the distance from the N-terminus yielding a larger (A) fragment and a smaller (B) fragment.27 In other "interstitial" collagens, e.g. type II collagen, the cleavage site is at a corresponding locus. There are many Gly/Ile and Gly/Leu sequences distributed throughout the component chains of type I collagen, yet only the bonds between residues 775-776 are cleaved by collagenases. Valuable information about collagenase specificity had been obtained through studies of small synthetic peptides that could be cleaved by collagenase but with a relatively high KM. Nevertheless, the results of these studies did not explain how collagenases cleave the natural triple helical substrate with a much lower KM and cleave denatured collagens more slowly than native collagens.28,29

Treating Rheumatoid Arthritis With Herbs Spices Roots

Treating Rheumatoid Arthritis With Herbs Spices Roots

Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.

Get My Free Ebook

Post a comment