PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

Abstract

Peroxisome proliferator‐activated receptors (PPARs) are abundantly expressed in human skin, with PPAR‐γ being the most intensively investigated isoform. In various ex vivo and in vivo models, PPAR‐γ‐mediated signalling has recently surfaced as an essential element of hair follicle (HF) development, growth and stem cell biology. Moreover, the availability of novel, topically applicable PPAR‐γ modulators with a favourable toxicological profile has extended the range of potential applications in clinical dermatology. In this review, we synthesize where this field currently stands and sketch promising future research avenues, focussing on the role of PPAR‐γ‐mediated signalling in the biology and pathology of human scalp HFs, with special emphasis on scarring alopecias such as lichen planopilaris and frontal fibrosing alopecia as model human epithelial stem cell diseases. In particular, we discuss whether and how pharmacological modulation of PPAR‐γ signalling may be employed for the management of hair growth disorders, for example, in scarring alopecia (by reducing HF inflammation as well as by promoting the survival and suppressing pathological epithelial‐mesenchymal transition of keratin 15 + epithelial stem cells in the bulge) and in hirsutism/hypertrichosis (by promoting catagen development). Moreover, we explore the potential role of PPAR‐γ in androgenetic alopecia, HF energy metabolism and HF ageing, and consider clinical perspectives that emanate from the limited data available on this so far. As this field of translational human hair research is still in its infancy, many open questions exist, for which we briefly delineate selected experimental approaches that promise to generate instructive answers in the near future.

Frontal fibrosing alopecia: state of the art and future directions

“…4 Peroxisome proliferator-activated receptors (PPAR) are nuclear hormone receptors that regulate gene transcription. 5 PPAR-γ is predominantly expressed in sebocytes, including the pilosebaceous units and the adipose tissue. Its activity is predominant during the anagen phase of hair cycle, being the key to control the action of TGFβ1 in supressing fibrogenesis.…”

“…Its activity is predominant during the anagen phase of hair cycle, being the key to control the action of TGFβ1 in supressing fibrogenesis. 5,6 Although deletions have been shown. 7 These transformations may account for the development of scarring alopecia and need further investigation on causative elements.…”

Towards a renaissance of dermatoendocrinology: Selected current frontiers

“…Dermatologists, skin biologists, endocrinologists and pharmacologists have long been fascinated by the complex effects of hormones on human and rodent skin in health and disease. [1][2][3][4][5][6][7][8] Ever since its inception, Experimental Dermatology has accompanied, mirrored and promoted the systematic exploration of dermatoendocrinology as a distinct, clinically highly relevant field of skin research. Beyond a conventional focus on steroid hormones, [9][10][11] early on, the journal has championed skin research into neuroendocrine signalling and non-steroid hormones.…”

“…[31] An additional example is the pilot study in this journal which strongly suggests that the cutaneous endocannabinoid system (negatively) regulates mitochondrial activity in human epidermal keratinocytes. [32] This only further attests to the power and significance of neurohormones in human skin physiology, [7,33] if one subsumes endocannabinoids under the rubric "neurohormones." These original research articles were recently rounded off by stimulating theoretical essays, such as on hormonal controls of hyperpigmentation in melasma, [34] on the role of melanocortin peptides or derivatives as potential future wound-healing therapeutics [30] and on the repurposing of neuropharmacological agents for targeting the skin neuroendocrine system, [35] whose full complexity is slowly emerging.…”

“…These original research articles were recently rounded off by stimulating theoretical essays, such as on hormonal controls of hyperpigmentation in melasma, [34] on the role of melanocortin peptides or derivatives as potential future wound-healing therapeutics [30] and on the repurposing of neuropharmacological agents for targeting the skin neuroendocrine system, [35] whose full complexity is slowly emerging. [7,33,36] With the current Focus Theme Issue dedicated to dermatoendocrinology, Experimental Dermatology continues this proud publication tradition and acknowledges the major advances that this rapidly evolving skin research arena has witnessed over the past decade. We start off with a very thought-provoking "cutaneous bacterial endocrinology" review by Racine et al [37] that portrays an intriguing, Following up on their previous exploration of this topic, [35] Soeberdt et al [38] then provide a pharmaceutical R&D perspective on how compounds that target neuroendocrine signalling in human skin and its appendages may be recruited and repurposed for the management of psoriasis, acne, alopecia areata, hyperhidrosis and atopic dermatitis and which formidable challenges one faces along this path.…”