Glycoprotein non-metastatic melanoma protein B (GPNMB) is a Type I transmembrane glycoprotein which has important roles in cancer and amyotrophic lateral sclerosis (ALS). In skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in pigmentation. Previously, we showed that GPNMB was highly expressed in keratinocytes from healthy donors, but decreased in vitiligo lesions. The function of keratinocyte-derived GPNMB is yet to be known. Therefore, we first confirmed GPNMB expression in cultured normal human epidermal keratinocytes, and oxidative stress (H2O2) down-regulated both membrane GPNMB and soluble GPNMB (sGPNMB) expression. Then, we found sGPNMB had protective effect to melanocytes against oxidative stress. Furthermore, sGPNMB was reported to have neuroprotective effect via CD44 receptor. However, after siRNA-mediated knockdown of CD44 in melanocytes, the protective effect of sGPNMB was not altered. These findings strongly suggest that the oxidative stress-induced down-regulation of GPNMB in keratinocytes is involved in vitiligo, taking it into account that GPNMB disappeared in epidermal keratinocytes of vitiligo skins and sGPNMB protected melanocytes from oxidative stress. Furthermore, not CD44 but another novel receptor may be expressed for the GPNMB extracellular fragment in melanocytes, suggesting that this novel pathway may represent a molecular target to improve vitiligo therapy.

Keratinocyte-derived glycoprotein non-metastatic melanoma protein B protects melanocytes from oxidative stress in a CD44-independent manner