Mechanical Stretching In Vitro Regulates Signal Transduction Pathways and Cellular Proliferation in Human Epidermal Keratinocytes

Abstract

Epidermal keratinocytes are continuously exposed to mechanical forces. The human skin surface can be thickened and enlarged by various stresses such as tissue expander or abrasive pressure. To investigate the mechanism of epidermal hyperproliferation by mechanical stress, keratinocytes were plated on flexible silicone dishes, which were continuously stretched by +20%. Stretching of cells for 24 h caused upregulation of 5-bromo-2'-deoxyuridine (BrdU)-positive cells to 200%-220% and activation of extracellular signal-regulated kinases (ERK)1/2. Inhibition of mitogen and ERK with U0126 and phosphoinositide 3-OH kinase attenuated BrdU incorporation and ERK1/2 activation. The EGF receptor kinase inhibitor and the calcium channel inhibitor also inhibited BrdU incorporation and the activation of ERK1/2. Twenty-four hours of stretching stimulated reporter activity driven by activator protein 1 (AP-1), induction of K6, and suppression of K10, which were inhibited by U0126. Our results indicate that mechanical stretching induces proliferative signals on human keratinocytes via induction of calcium influx, phosphorylation of epidermal growth factor receptor (EGFR), and ERK1/2. These mechanisms may contribute to the hyperproliferative nature of the epidermis, which is mechanically stretched by various stimuli.