PATHOPHYSIOLOGY OF THE CYCLICAL EPIDERMOLYTIC PALMOPLANTAR KERATODERMA (EPPK) IN THE KERATIN 9 MOUSE MODEL
Shen, Joseph YuHung
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Keratin 9 (KRT9/Krt9) is a type I intermediate filament protein that is constitutively expressed in the suprabasal layer of the thicker and specialized epidermis of the palmoplantar skin. Mutations at the KRT9/Krt9 locus cause epidermolytic palmoplantar keratoderma (EPPK), a rare autosomal dominant disorder characterized by diffuse palmoplantar keratoderma. Krt9-/- mice exhibit hyperpigmented calluses on the major stress-bearing footpads that form, progress, and slough off in a precise cyclical fashion (Fu et al., 2014), and thus offer a useful model to study the pathophysiology of EPPK related to KRT9/Krt9 mutations. Previously, our laboratory has shown that oxidative stress associated with hypoactive NRF2, a transcription factor that regulates the cellular stress response, precedes the development of lesions in Krt16-/- mice, a model of non-epidermolytic palmoplantar keratoderma (NEPPK) (Kerns et al., 2016). The finding of increased oxidative stress associated with impairment of NRF2 activity in a model of NEPPK raised the possibility of similar alterations in EPPK. Here, we conducted an in-depth analysis of lesion progression in the Krt9-/- mouse model that expanded the work of Fu et al. and enabled us to pinpoint critical time points to assess the status of NRF2 signaling and NRF2-mediated stress-related proteins. Biochemical and histological analysis of pre-lesional paw skin revealed normal NRF2 activity and redox status. Moreover, treatment with an NRF2 inducer failed to impact lesion formation in Krt9-/- mice. These findings suggest that unlike NEPPK, oxidative stress and hypoactivity of NRF2 may not be a major driving force in EPPK. Thus, although EPPK and NEPPK share the common feature of palmoplantar keratoderma, distinct molecular mechanisms underlie each disorder.