TSH is a novel neuroendocrine regulator of selected keratins in the human hair follicle

Abstract

2Keratins and keratin-associated proteins (KAPs) constitute the major structural protein components of the hair. Regulation of their expression is critical for proper hair follicle (HF) structure and function [1]. Therefore, it is important to fully elucidate the controls that regulate keratin expression. Although it is accepted that the expression of selected keratin genes underlies endocrine controls [1,2], our understanding of the complex regulation of keratin expression remains rather fragmentary. To better elucidate this regulation, human skin and HF organ culture offer an instructive, physiologically relevant research tool [1,3].In particular, very little is known on the neuroendocrine controls of keratin transcription. The importance of the latter is highlighted by the recent discovery that the "pituitary" neuropeptide hormone, prolactin, which is also expressed by human HFs, potently regulates the expression of selected human keratins on the gene and protein level [3]. Moreover, microarray analyses had provided first clues that thyroid stimulating hormone (TSH) and its proximal regulator in the hypothalamic-pituitary-thyroid axis, thyrotropin-releasing hormone (TRH), might operate as previously unsuspected modulators of human hair keratin and KAP gene transcription in situ [4][5][6]. Also, we had recently found that TSH upregulates keratin K5 gene expression and protein synthesis as well as K14 transcription in human epidermis [4]. Therefore, we have asked whether TSH operates as a novel neuroendocrine regulator of human keratins in situ, using microdissected, organ-cultured human scalp HFs as a physiologically and clinically relevant assay systems [3][4][5]. This was complemented by studying the effect of TSH on keratin expression in cultured human outer root sheath (ORS) keratinocytes (KCs).Anagen VI HFs were isolated from normal frontotemporal scalp skin obtained after written informed consent from three healthy females undergoing routine face-lift surgery, as 3 previously described [4,5], adhering to Helsinki guidelines and under a licence from the ethics committee of the University of Lübeck. HF mRNA extracts from one female patient were subjected to quantitative real time PCR (qPCR) for selected hair keratin genes after 24 hrs treatment with TSH (100 mU ml -1 ) or vehicle. For immunohistochemical analysis, isolatedHFs from additional two female patients were organ cultured for 6 days as described previously [3,4], and expression of keratins K6, K14, K17, K31, K32, K85 and MSX-2 was studied with our previously published basic immunohistology protocols [3,4] ( These qPCR analyses demonstrated that TSH downregulated transcription of KRT31 and KRT32 genes (Fig. 1A). In these qPCR analyses, KRT35 transcription was largely unaffected by TSH. Instead, transcription of its type II counterpart keratin gene, KRT85 [2], was downregulated (Fig. 1A). 4Immunohistochemical studies on TSH treated HFs confirmed the downregulation of the hair keratins also at the protein level ( Fig. 2A-C): K31 immunoreactivity, loc...

Is thyrotropin-releasing hormone a novel neuroendocrine modulator of keratin expression in human skin?

“…4 Thyroid-stimulating hormone (thyrotropin, TSH) was also found to modulate keratin gene expression in the epidermis and HFs. 5,6 This was underscored by preliminary gene profiling evidence that another neuropeptide hormone, thyrotropin-releasing hormone (TRH), which is also produced by HFs, may interfere and regulate selected intrafollicularly expressed keratins and keratin-associated proteins. 7 Because TRH is a potent stimulator of human hair growth in situ, 7 and also stimulates hair pigmentation, 8 we wanted to elucidate whether TRH acts as a novel regulator of keratin expression in situ.…”

“…In fact, TSH administration to cultured human HFs modulates expression of several keratins in a somewhat comparable manner to TRH, such as K14, K17 and K85. 6 Clinically, it is well known that patients with hyper-or hypothyroidism show significant hair phenotypes, most prominently telogen effluvium. 14,15 Many of these patients also have conspicuous hair shaft abnormalities, including thinning of hair shafts along with dryness, brittleness and reduced tensile strength.…”

“…Interest in the neuroendocrine control of keratin expression in human skin has been invigorated by recent evidence that the neuropeptide hormone, prolactin, profoundly impacts on the expression of keratins such as K5, K6, K14, K15, K19 and K31 in human hair follicles (HFs) . Thyroid‐stimulating hormone (thyrotropin, TSH) was also found to modulate keratin gene expression in the epidermis and HFs . This was underscored by preliminary gene profiling evidence that another neuropeptide hormone, thyrotropin‐releasing hormone (TRH), which is also produced by HFs, may interfere and regulate selected intrafollicularly expressed keratins and keratin‐associated proteins…”

Harnessing neuroendocrine controls of keratin expression: A new therapeutic strategy for skin diseases?

“…B: TSH downregulates K85 expression in the precortical hair matrix and hair cortex. Reproduced from . Scale bars = 50 µm.…”

“…Not only are skin and its appendages key target tissues for multiple different hormones, for which they express cognate high‐affinity receptors, but they also are very important non‐classical sites of hormone synthesis and metabolism . This includes a surprisingly large number of classical “neuroendocrine” ligands, such as melatonin , prolactin , thyrotropin‐releasing hormone (TRH) , thyrotropin (TSH) , corticotropin‐releasing hormone (CRH) , proopiomelanocortin products such as alpha‐melanocyte stimulating hormone (α‐MSH), adrenocorticotropic hormone (ACTH), and β‐endorphin, catecholamines, and acetylcholine .…”