549 Disappearance of keratinocyte expression of Glycoprotein Non-metastatic B (GPNMB) / Osteoactivin in vitiligo – possible involvement of Th1/Th 17 cytokines

Abstract

GPNMB is a highly glycosylated type I transmembrane protein, which is known to be expressed in many cell types with multiple functions including cell adhesion, stress protection, and stem cell maintenance. In the skin, melanocyte GPNMB is suggested to mediate pigmentation through melanosome formation, but details of its expression and function in epidermal keratinocytes are not well characterized. We previously confirmed the predominant expression of GPNMB at a lower calcium condition in cultured normal human epidermal keratinocytes (NHEK). Histological staining showed that GPNMB was expressed in the basal layer of normal skins, but disappeared completely in vitiligo. To consider the reason for the loss of epidermal GPNMB in vitiligo, we examined the effects of candidate cytokines and chemokines in vitiligo development on GPNMB expression as well as on the formation of soluble GPNMB (sGPNMB). We demonstrated that IFN-γ downregulated keratinocyte GPNMB following JAK2/STAT1 signaling axis. IL-17A also inhibited its expression, whereas CXCL10, CXCL12 and CXCL16 showed no effect. NHEK secreted sGPNMB accounting about 4-5% of the total GPNMB. ADAM 10-selective inhibitor GI254023X decreased the sGPNMB production at the same extent as BB-94 with broad spectrum, suggesting the involvement of ADAM 10 in shedding GPNMB. Neither IFN-γ nor IL-17A was involved in this shedding process. These findings suggest that keratinocyte GPNMB could be a new target in vitiligo although further investigation on the roles of keratinocyte GPNMB to maintain functional melanocytes is needed.