Differential Expression of Hedgehog and Snail in Cutaneous Fibrosing Disorders

Abstract

OBJECTIVES To examine Hedgehog signaling in cutaneous fibrosing disorders for which effective approved therapies are lacking, expand our knowledge of pathophysiology, and explore the rationale for targeted inhibition. METHODS Stain intensity and percentage of cells staining for Sonic hedgehog (Shh), Indian hedgehog (Ihh), Patched (Ptch), glycogen synthase kinase 3 β (GSK3-β), β-catenin, and Snail were evaluated in human skin biopsy specimens of keloid, hypertrophic scar (Hscar), scleroderma, nephrogenic systemic fibrosis (NSF), scar, and normal skin using a tissue microarray. RESULTS Ihh, but not Shh, was detected in a significantly larger proportion of cells for all case types. Ptch, GSK3-β, and β-catenin showed a gradient of expression: highest in NSF and keloid; moderate in normal skin, scar, and Hscar; and lowest in scleroderma. Snail expression was binary: low in normal skin but high in all fibrosing conditions studied. CONCLUSIONS Differential overexpression of Hedgehog and Snail in cutaneous fibrosing disorders demonstrates a role for targeted inhibition. Ptch, GSK3-β, and β-catenin can help differentiate scleroderma from NSF in histologically subtle cases. Differences in expression between keloid and hypertrophic scar support the concept that they are pathophysiologically distinct disorders. Our findings implicate Snail as a target for the prevention of fibrogenesis or fibrosis progression and may offer a means to assess response to therapy.