Consequences of Elastolysis - Extracellular Matrix Degradation - page 237

The cathepsins are the most potent elastases known (Chapman et al. 1997 ;
Yasuda et al. 2004 ), especially cathepsins K and V (Table 9.3 ). Cathepsin K is
most active at acidic pH (within lysosomes), and although found extracellularly on
occasion it is not stable at neutral pH. Cathepsins S and L, in contrast, are both
stable in the extracellular environment at neutral pH. Perhaps the greatest contribu-
tion to elastolysis in vivo is made by the nonelastolytic cathepsin C (DPPI), which
is required for the activation of neutrophil-derived serine proteinases. The cysteine
cathepsins are inhibited by a superfamily of inhibitors, termed the cystatins, of
which cystatin C is the most prevalent (Abrahamson et al. 1987 ).
The relative contribution of cysteine cathepsins versus MMPs versus serine
proteinases both in vitro and in vivo remains difficult to elucidate (Chapman and
Stone 1984 ; Punturieri et al. 2000 ; Filippov et al. 2003 ). In vitro assays attempting
to determine which macrophage-derived elastases are operative have provided
conflicting results. The expression of MMPs versus cathepsins changes over time
such that different results will be obtained depending on which time point is used.
With respect to emphysema, all four elastolytic cysteine cathepsins (S, L, V, and K)
can be expressed by alveolar macrophages and therefore could theoretically con-
tribute to elastic fiber degradation within the lung. IL-13 transgenic mice develop
airspace enlargement characteristic of emphysema and display a several-fold
increase in cathepsin S expression (Zheng et al. 2000 ). However, subsequent
study of Cat S / mice in the cigarette smoke-exposure model failed to show
protection (SDS, unpublished).
Elastolytic cathepsins significantly contribute to atherosclerotic disease. The
in vivo contributions of these enzymes have been best characterized in the
ApoE / mouse model of atherosclerotic plaque and rupture. CatS / , CatK / ,
and Cystatin C-deficient mice are all involved in plaque formation and rupture in
this model (Lutgens et al. 2007 ). The exact source and contributions of the
cathepsins to atheroma remain unclear. Smooth muscle cells, endothelial cells,

Table 9.3 Relative potency of selected elastases
Proteinase Rank Reference

Cathepsin K
pH 5.5 10 Bromme et al. ( 1996 )

pH 7.4 6 Bromme et al. ( 1996 )

Pancreatic elastase 8 Baugh and Travis ( 1976 )

Cathepsin L
pH 5.5 5 Mason et al. ( 1986 )

Cathepsin S
pH 5.5 7 Xin et al. ( 1992 )

pH 7.4 2.5 Xin et al. ( 1992 )

Neutrophil elastase 3 Baugh and Travis ( 1976 )

MMP2 2.5 Senior et al. ( 1991 )

Proteinase-3 1.5 Kao et al. ( 1988 )

MMP7 1.5 Murphy et al. ( 1991 )

MMP12 1 Senior et al. ( 1991 )

MMP9 1 Senior et al. ( 1991 )

Table reproduced with permission from Chapman et al. ( 1997 )