Ectodysplasin-A2 induces apoptosis in cultured human hair follicle cells and promotes regression of hair follicles in mice

Ectodysplasin is a ligand of the TNF family that plays a key role in ectodermal differentiation. EDA-A1 and EDA-A2 are two isoforms of ectodysplasin that differ only by the insertion of two amino acids and bind to two different receptors, ectodysplasin A receptor (EDAR) and ectodysplasin A2 receptor (EDA2R), respectively. Mutations of EDA-A1 and its receptor EDAR have been associated with hypohidrotic ecodermal dysplasia (HED). However, the role of EDA-A2 and the expression pattern of EDA2R in human hair follicles and in the mouse hair growth cycle have not been reported. In this study, we first investigated the expression of EDA2R in human hair follicles and in cultured follicular cells. EDA2R was strongly expressed in outer root sheath (ORS) cells and weakly expressed in dermal papilla (DP) cells. EDA-A2 induced the apoptosis of both ORS cells and DP cells via the activation of cleaved caspase-3. In addition, EDA2R was highly expressed in the late anagen phase compared with other phases in the hair growth cycle. Moreover, EDA-A2 induced apoptosis in cultured human hair follicle cells and in the mouse hair growth cycle, causing the premature onset of the catagen phase. Collectively, our results suggest that EDA-A2/EDA2R signaling could inhibit hair growth, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of hair loss.