MMP/ADAM inhibitors: therapeutic potential for psoriasis

Abstract

Psoriasis is a common and chronic skin disease characterised by skin inflammation and hyperproliferation of epidermal keratinocytes, but the pathogenesis remains to be elucidated. Recently, anticytokine therapy, for example, the blockade of tumour necrosis factor (TNF)-α, was approved as treatment for psoriasis, indicating that TNF-α is a main mediator of chronic skin inflammation in psoriatic lesions. TNF-α is produced in diverse immune cells and keratinocytes and released after ectodomain shedding. TNF-α converting enzyme (TACE/ADAM17) is the primary enzyme that cleaves membrane-bound TNF-α at the ectodomain site and is classified within the disintegrin and metalloproteinase (ADAM) family. Hyperproliferation of keratinocytes is associated with activation of epidermal growth factor receptor (EGFR). The EGFR ligands are also generated in a membrane-bound form and released after ectodomain shedding by ADAMs and matrix metallo-proteinases (MMPs). Herein, the pathological and physiological implication of MMP/ADAM in the pathogenesis of psoriasis and the therapeutic potential of MMP/ADAM inhibitors are discussed.