Biology Reference
In-Depth Information
disease. For example, cystatin C levels are significantly reduced in atherosclerotic
and aneurysmal aortic lesions (Shi et al.
1999
). Cystatin C deficiency in a mouse
model of atherosclerosis significantly increased the tunica media elastic lamina
fragmentation, decreased medial size, and increased smooth muscle cell and colla-
gen content in aortic lesions (Sukhova et al.
2005
). This indicates that extracellular
cathepsin activities increase when the levels of their endogenous extracellular
inhibitors decrease.
ECM degradation does not have to occur extracellularly (Everts et al.
1996
).
Various cell types are effective in endocytosing ECM proteins (e.g., macrophages,
histiocytes, antigen presenting cells, and multinucleated cells including osteoclasts,
fibroblasts, endothelial and epithelial cells). Endocytosis is discussed in detail in
Chap. 4. ECM-containing phagosomes fuse with cathepsin-containing lysosomes,
which leads to a rapid degradation of the matrix material. Inhibition of lysosomal
cathepsins in phagocytes leads to an accumulation of undegraded matrix within the
endosomal/lysosomal compartment. Osteoclasts and fibroblasts deficient in cathep-
sin K, for example, or cells treated with cathepsin K inhibitors accumulate non-
degraded collagen fibrils detectable by electron microscopy (Everts et al.
2003
). It
is likely that the uptake of ECM is at least partially preceded by an extracellular
predigest of the matrix by either secreted cathepsins and/or matrix- and membrane-
associated metalloproteases. Figure
2.2
summarizes the interactions between cathe-
psins and the ECM under physiological and pathological conditions.
Fig. 2.2 Schematic representation of extracellular matrix conditions supportive or prohibitive for
cathepsin activity. Neutral pH, oxidative environment, and the abundance of endogenous cathep-
sin inhibitors such as cystatins prevent or strongly limit the activity of secreted cathepsins (
left
side
). Under certain pathological (inflammatory) conditions the extracellular matrix is acidified
and cystatin expression is downregulated (
right side
). This provides optimal condition for cathe-
psins to be active and allows the processing of secreted procathepsins into catalytically active
forms. Phagocytosis is possible under both conditions and allows indirectly the degradation of the
extracellular matrix by lysosomal cathepsins
