Androgens influence expression of matrix proteins and proteolytic factors during cutaneous wound healing

Abstract

Excessive proteolytic activity is a feature of chronic wounds such as venous ulcers, in which resolution of the inflammatory response fails and restorative matrix accumulation is delayed as a consequence. The inflammatory actions of native androgens during the healing of acute skin wounds have lately been characterized. We have now investigated the hypothesis that such activities may impact upon the balance between anabolic and catabolic processes during wound healing. We report that wound deposition of both type I collagen and fibronectin is increased in castrated rats compared with control animals. This response is accompanied by early increases and later decreases in overall wound levels of the key collagenolytic enzymes, matrix metalloproteinase (MMP)-1 and MMP-13. Moreover, the activities of MMP-2 and MMP-9, two further enzymes that contribute to collagen digestion during venous ulceration, were significantly decreased in the wounds of castrated rats. Additional analyses provide evidence that androgens directly stimulate dermal fibroblast collagen production, which supports the suggestion that increased wound collagen deposition in androgen-deprived rats results from reduced matrix degradation (as opposed to enhanced matrix protein biosynthesis). Androgen-mediated dysregulation of the parallel processes of collagen deposition and turnover may underscore the delayed healing of cutaneous wounds in elderly male patients and further contribute to the increased incidence of non-healing wounds in this population.

17β-Estradiol Inhibits Wound Healing in Male Mice via Estrogen Receptor-α

“…MMP-2 is implicated in the pathogenesis of chronic leg 31 and diabetic foot 32 ulceration and in the impairment of healing by aging 15 and androgens, 33 while limiting the activity of MMP-2 (and MMP-9) has been proposed as a mechanism by which healing might be improved. 34 We thus inferred that estrogens might create a degradative environment in the dermis that may contribute to delayed repair following subsequent injury, and indeed, we found that the similar induction of MMP-2 activity in day 3 wounds in estrogen-treated animals was accompanied by reduced accumulation of collagen.…”

Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression

“…Earlier studies by Ashcroft and colleagues, using surgical or chemical castration, have found that androgens were able to inhibit cutaneous wound healing, possibly by modulating inflammatory responses, matrix deposition, and keratinocyte function (1,(8)(9)(10). However, the in vivo role of androgens/AR signals in different cell types involved in the wound-healing process remains unclear.…”

“…The rate of collagen deposition is determined by the balance of collagen synthesis and degradation. Interestingly, the activity of MMP-1 (collagenase I) and MMP-13 (collagenase III) was reduced in castrated rats in the later stages of wound healing (9). Because macrophages express several proteinases and their activators/inhibitors (46)(47)(48)(49), it is possible that macrophage AR promotes the expression or activation of proteinases to enhance collagen degradation.…”

Effect of long-term topical application of dehydroepiandrosterone (DHEA) and oral estrogens on morphology, cell proliferation, procollagen A1 and androgen receptor levels in rat skin

“…Although these effects were suggested to occur via DHEA conversion to estrogens (24), our findings suggest an androgenic effect in the stimulatory action of DHEA on procollagen A1 expression, in the context of a normal hormonally deprived skin model. Supporting this explanation, studies in animal models and in the human have demonstrated the stimulatory effect of testosterone and DHT on dermal collagen content (32,58,59), whereas, in wound healing, the role of androgens could be different (60,61). However, neutral or a beneficial role of androgens in stimulating the production of type 1 collagen protein have been described in scratch-wounded and intact rat dermal fibroblasts, respectively (59).…”