Dermatological diseases range from minor cosmetic problems to life-threatening conditions, as seen in some severe disorders of keratinization and cornification. These disorders are commonly due to abnormal epidermal differentiation processes, which result in disturbed barrier function of human skin. Elucidation of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis is therefore of great importance for the understanding and
therapy of these disorders. Much of the barrier function of human epidermis against the environment is provided by the cornified cell envelope (CE), which is assembled by
transglutaminase (TGase)-mediated cross-linking of several structural
proteins and
lipids during the terminal stages of normal keratinocyte differentiation. The major constituents of the stratum corneum and the current knowledge on the formation of the stratum corneum will be briefly reviewed here. The discovery of mutations that underlie several human diseases caused by genetic defects in the
protein or
lipid components of the CE, and recent analyses of mouse mutants with defects in the structural components of the CE, catalyzing
enzymes, and
lipid processing, have highlighted their essential function in establishing the epidermal barrier. In addition, recent findings have provided evidence that a disturbed
protease-
antiprotease balance could cause faulty differentiation processes in the epidermis and hair follicle. The importance of regulated proteolysis in epithelia is well demonstrated by the recent identification of the SPINK5
serine proteinase inhibitor as the defective gene in
Netherton syndrome,
cathepsin C mutations in
Papillon-Lefevre syndrome,
cathepsin L deficiency infurless mice, targeted ablation of the
serine protease Matriptase/MTSP1, targeted ablation of the
aspartate protease cathepsin D, and the phenotype of targeted epidermal overexpression of stratum corneum chymotryptic
enzyme in mice. Notably, our recent findings on the role of
cystatin M/E and
legumain as a functional dyad in skin and hair follicle cornification, a paradigm example of the regulatory functions exerted by epidermal
proteases, will be discussed.