Towards dissecting the pathogenesis of retinoid-induced hair loss: All-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-β2 in the dermal papilla

Diffuse hair loss ranks among the most frequent and psychologically most distressing adverse effects of systemic therapy with retinoids, which severely limits their therapeutic use even where clinically desired. Since the underlying mechanisms of retinoid-induced effluvium are as yet unknown, we have investigated the influence of the prototypic retinoid all-trans retinoic acid (ATRA, tretinoin) on the growth of human scalp hair follicles (HF) in culture. HF in the anagen VI stage of the hair cycle were cultured in the presence of 10^-8 or 10^-10 M ATRA. Compared with controls, hair shaft elongation declined significantly already after 2 d in the ATRA-treated group, and approximately 80% of the ATRA-treated HF had prematurely entered catagen-like stage at day 6, compared with 30% in the control group. This corresponded to an upregulation of apoptotic and a downregulation of Ki67-positive cells in ATRA-treated HF. Since transforming growth factor (TGF)-β has been implicated as a key inducer of catagen, we next studied whether ATRA treatment had any effect on follicular expression. TGF-β2 immunoreactivity was detected in the outer root sheath of anagen VI scalp HF. In catagen follicles, TGF-β2 was also expressed in the regressing epithelial strand. After 4 d of ATRA treatment, TGF-β2 was significantly upregulated in anagen HF in the dermal papilla (DP) and the dermal sheath, 7, and TGF-β neutralizing antibody partially abrogated at RA induced hair growth inhibition. Real-time PCR confirmed a significant upregulation of TGF-β2 transcripts in ATRA-treated hair bulbs. This study is the first to provide direct evidence that ATRA can indeed induce a catagen-like stage in human HF and suggests that this occurs, at least in part, via upregulation of TGF-β2 in the DP. Therefore, topical TGF-β2/TGF-β receptor II antagonists deserve to be explored for the prevention and management of retinoid-induced hair loss.