Some cathepsins have been detected in different regions of the eye. The optic nerve and the cornea express cathepsins A, B, D, and L, and the choroid expresses cathepsin S.
35 In the retina, the presence of cathepsin D
36 37 38 and cathepsin B has been reported.
35 36 Cathepsins are proteases located in the lysosomes. For years their biological functions have been circumscribed to unspecific intracellular protein degradation. Current evidence points to a role of lysosomes and, more specifically, of cathepsins in apoptosis. In fact the lysosomal pathway of apoptosis is a new phenomenon that is widely recognized.
12 39 To promote cell death, these proteases must be released from the lysosomes. Lysosomal permeabilization is facilitated by sphingosine, a lipid whose overexpression is linked to apoptosis.
40 Our array study
8 revealed that the mRNAs of some enzymes of the sphingosine metabolism were soon upregulated after IONT (sphingosine kinase 1 and sphingosine-1-phosphate lyase) and IONC (sphingosine kinases 1 and 2). The upregulation of these enzymes increases the amount of cytosolic sphingosine, which may eventually cause lysosomal permeabilization.
40 41 The role of cathepsins in apoptosis is twofold. First, they act as proteases, cleaving and consequently activating caspases. Second, they act on the mitochondria to induce mitochondrial dysfunction.
12 39 42 Cathepsin B is essential in different models of apoptosis through the generation of reactive oxygen species and the release of cytochrome
c from the mitochondria.
10 32 33 It has been related as well to the activation of caspase 11.
34 Our array data showed that the mRNA of several cathepsins were upregulated in the retina after IONT (cathepsins B, C, H, L, S, and Z) and after IONC (cathepsins C and Z). The present studies show that the precursor and active forms of cathepsin B and C proteins are upregulated after both ON injuries and that both are expressed by RGCs. Interestingly, the upregulation of the active form is stronger after IONT than IONC, and this may be responsible in part for the quicker RGC degeneration observed anatomically after transection than after crush (Parrilla-Reverter G, et al.
IOVS 2006;47:ARVO E-Abstract 1248). Because both cathepsins are upregulated and are active earlier (12 hours) than occurs with the upregulation of caspase 3 (48 hours) and concomitantly caspase 11 (12 hours) and because both caspases are activated by cathepsins, it is tempting to speculate that the upregulation of cathepsins B and C in the axotomized retinas is an early event of apoptosis caused by optic nerve injury.