Although cutaneous wounds are known to heal more slowly in elderly men than in elderly women –and this observation had been linked to androgens – the exact role of androgens in the wound healing process is not clear. Researchers at the University of Rochester have now shown that, in general androgen receptor (AR) knockout mice, wound healing was faster than in wild type litter mates: re-epithelialisation and collagen deposition were also found to be enhanced in knockout versus wild type animals. Because serum testosterone levels are significantly reduced in the knockout animals and androgens are known to regulate cellular activities through AR-independent pathways, the team subcutaneously implanted dihydrotestosterone (DHT) pellets into the knockout mice to restore their serum androgen levels. The observation that DHT implantation did not reverse the acceleration of wound healing in the knockout animals suggests that AR-dependent pathways are critical for the accelerated wound-healing phenotype.
Using cell-specific AR knockout mice, the team went on to show that it is AR on infiltrating macrophages, rather than on resident keratinocytes or dermal fibroblasts, that plays a critical role in delaying wound healing and collagen deposition but that AR on keratinocytes and fibroblasts plays an opposing role in the regulation of re-epithelialization. Examination of inflammatory mediators showed that increased local TNF-α production following AR activation on macrophages plays a critical role in suppressing wound healing.
Topical application of ASC-J9, an anti-AR compound that causes increased AR degradation and reduced AR transactivation, was shown to accelerate wound healing. Earlier in vitro and in vivo studies have shown that ASC-J9 reduces AR-promoted tumour growth in liver and bladder cancer as well as AR-mediated spinal and bulbar muscular atrophy, with little influence on serum testosterone concentrations. The present study, which is published in the Journal of Clinical Investigation, suggests that topical treatment with ASC-J9 also has the potential to be effective in promoting wound healing.
ASC-19 is currently undergoing clinical trials for the treatment of acne and alopecia.