Biology Reference
In-Depth Information
Chapter 2
Role of Cysteine Cathepsins in Extracellular
Proteolysis
Dieter Bromme and Susan Wilson
Abstract Cysteine cathepsins are lysosomal proteases with housekeeping as well
as highly specialized functions. Although their activities are optimal at lysosomal
acidic and reducing conditions, cathepsins can significantly contribute to the deg-
radation of the extracellular matrix. This may happen under physiological condi-
tions as in cathepsin K-mediated bone resorption or under pathological conditions.
Extracellular matrix degradation can occur extracellularly by the secretion of
cathepsins or intracellularly following the endocytosis of matrix material. Under
physiological conditions, the extracellular matrix is safeguarded against cathepsin
activities by its neutral pH, oxidative environment, and high levels of potent
endogenous cathepsin inhibitors. However, these barriers can be overcome by
pericellular acidification and pathophysiologically reduced anticathepsin concen-
trations. Whereas matrix metalloproteases are primarily responsible for the homeo-
stasis of the extracellular matrix, cysteine proteases contribute to its destruction
under disease conditions. The development of cathepsin inhibitors as anti matrix-
degrading drugs appears to be a successful strategy.
2.1
Introduction
Proteases represent 1-4% of the genes per genomes sequenced to date and are found
in all known life forms from viruses to mammalia. The human genome expresses
more than 670 proteases from which about 31% are serine proteases, 25% cysteine
proteases, 33% metalloproteases, and 4% aspartic proteases. The remainder are
threonine proteases and proteases of other or unknown mechanisms (
http://merops.
sanger.ac.uk
)
. Their functions include food processing in the gastrointestinal sys-
tem (e.g., digestive proteases in saliva, stomach, and intestines), intracellular
housekeeping (e.g., lysosomal proteases), one-way signal transduction (e.g., caspases
D. Bromme (
*
) and S. Wilson
Department of Oral and Biological Sciences, University of British Columbia, 2100 Wesbrook
Mall, Vancouver, BC, Canada V6T 1Z3
e-mail: dbromme@interchange.ubc.ca
