The Thyroid Hormone Inactivator Enzyme, Type 3 Deiodinase, Is Essential for Coordination of Keratinocyte Growth and Differentiation

Mancino, Giuseppina; Sibilio, Annarita; Luongo, Cristina; Cicco, Emery Di; Miro, Caterina; Cicatiello, Annunziata Gaetana; Nappi, Antonio; Sagliocchi, Serena; Ambrosio, Raffaele; Stefano, Maria Angela De; Girolamo, Daniela Di; Porcelli, Tommaso; Murolo, Melania; Saracino, Federica; Perruolo, Giuseppe; Formisano, Pietro; Stornaiuolo, Mariano; Dentice, Monica

doi:10.1089/thy.2019.0557

Cited by 17 publications

(25 citation statements)

References 47 publications

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“…Moreover, alterations in energy metabolism is a major contributor to other disease-related aging features (79), including lifespan regulation (80,81). The upregulation of specific components related to mitochondrial energy metabolism in white hairs suggests that energy metabolism regulates not only hair growth as previously demonstrated (12,82,83) but also HS graying biology.…”

Section: Discussionmentioning

confidence: 84%

Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

Rosenberg

Rausser

Ren

et al. 2020

Preprint

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Hair graying is a universal hallmark of aging 1 but its mechanisms are insufficiently understood 2 and its reversibility in humans remains uncertain. Moreover, while psychological stress accelerates human biological aging 3,4 and triggers hair graying in animals 5 , no prior study has longitudinally examined the stress-to-hair graying connection in humans. Here we develop an approach to quantitatively profile natural graying events and their associated proteomic signatures along individual human hairs, resulting in a quantifiable physical timescale of aging.Using this approach, we identify white hairs that naturally regain pigmentation within days to weeks in healthy young individuals across sex, ethnicities, ages, and body regions, demonstrating that human hair graying is naturally reversible. Proteomic analysis of matched dark and white hairs replicated across two independent experiments show that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Coordinated graying and reversal also occur simultaneously across multiple scalp hair follicles of a person, suggesting that unknown systemic factors influence hair graying patterns. Combining hair pigmentation profiling and proteomics at the single hair shaft level, we also report hair graying and reversal occurring in parallel with behavioral and psychological stressors. A computational simulation of life-long and stress-induced hair graying suggests a threshold-based mechanism for the rapid reversibility of graying. Together, these findings document the reversibility of hair graying in humans and provide a new model to examine the modifiability of human aging.

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Section: Discussionmentioning

confidence: 84%

Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

Rosenberg

Rausser

Ren

et al. 2020

Preprint

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“…29,50,51 The plasma membrane transport of THs is facilitated and regulated by specialized, energy-dependent transporter systems, 52 while TH metabolism and thereby local TH activity in a given tissue is enzymatically controlled via differentially expressed deiodinases. [53][54][55][56] All of these elements are present and active in human skin (see below).…”

Section: Thyroid Hormone ( Th) B I Ologymentioning

confidence: 99%

“…Given the sweeping functional repercussions of direct and indirect TR-mediated signalling for mammalian skin homoeostasis and function, it is not surprising that intracutaneous TH metabolism underlies tight regulation by deiodinases, for example via the intraepidermal activity of the TH-inactivating type 3 deiodinase, which may function as an important coordinator of keratinocyte proliferation and differentiation in murine epidermis. 53,54 Unfortunately, with the notable exception of keratinocytes and their progenitor cells, 86 the impact of TH on most other resident cell populations of human skin is unknown or remains very incompletely explored. However, the observation that hyperthyroidism can be associated with skin hyperpigmentation (Table 1)…”

Section: Cutaneous Th B I Ologymentioning

confidence: 99%

“…160 Finally, mice that selectively lack oncofetal protein type 3 deiodinase, the TH-inactivating enzyme in the epidermis, show delayed WH. 53 The WH process requires coordination of multiple cellular functions and multiple cell types to properly execute this pro- 166 while hypothyroid patients have asymptomatic small-fibre sensory neuropathy, which impairs WH. 71 Thus, while the final verdict of T4 effects on human WH is still out, the vast majority of currently available indications suggests that this may well be the "bride" for whom the "princess" of translational WH research have long been looking.…”

Section: Thyroid Hormone S and Wound He Alingmentioning

confidence: 99%

“…THs rank among the most potent hormones in vertebrate biology, and the toxicity of chronically increased serum levels of T3 and/ or T4, 211 independent of whether they are medication-induced or result from excessive TH secretion by the thyroid gland, is welldocumented ( Table 2). The high expression and activity level of deiodinases in epidermis and endothelial cells 53,54 would be expected to reduce the risk of both, local overstimulation of TRs and high levels of systemic absorption of topically applied T4. Moreover, temporary topical T4 administration through the intact epidermal barrier in a relatively small skin area may not lead to a measurable increase in serum T3/T4 levels.…”

Section: P Otential Toxi Cit Y and C Arcinog Eni C Ris K S A Sso Cimentioning

confidence: 99%

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Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

Paus

Ramot

Kirsner

et al. 2020

Experimental Dermatology

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Dermatologists have used natural or synthetic agonists of glucocorticoid, vitamin D or retinoid nuclear hormone receptors, both systemically and topically, for decades in the management of skin diseases. In fact, the introduction of glucocorticoids, calcitriols and retinoids into the clinic each constituted landmark progress in skin therapies, and the range of dermatological indications for each of these distinct classes of chemicals rapidly expanded after they became widely accepted in clinical practice. 1,2 Given the success of these agents, it is surprising that a fourth class of potent nuclear hormone receptor agonists has not been developed as part of the therapeutic arsenal of dermatology: endogenous and synthetic thyroid hormone receptor (TR) ligands. 3 This "Cinderella status" of these peptide hormones among endocrinological dermatotherapy is even more surprising in view of

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Thyroid hormone action in epidermal development and homeostasis and its implications in the pathophysiology of the skin

Mancino

Miro

Cicco

et al. 2021

J Endocrinol Invest

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Thyroid hormones (THs) are key endocrine regulators of tissue development and homeostasis. They are constantly released into the bloodstream and help to regulate many cell functions. The principal products released by the follicular epithelial cells are T3 and T4. T4, which is the less active form of TH, is produced in greater amounts than T3, which is the most active form of TH. This mechanism highlights the importance of the peripheral regulation of TH levels that goes beyond the central axis. Skin, muscle, liver, bone and heart are finely regulated by TH. In particular, skin is among the target organs most influenced by TH, which is essential for skin homeostasis. Accordingly, skin diseases are associated with an altered thyroid status. Alopecia, dermatitis and vitiligo are associated with thyroiditis and alopecia and eczema are frequently correlated with the Graves’ disease. However, only in recent decades have studies started to clarify the molecular mechanisms underlying the effects of TH in epidermal homeostasis. Herein, we summarize the most frequent clinical epidermal alterations linked to thyroid diseases and review the principal mechanisms involved in TH control of keratinocyte proliferation and functional differentiation. Our aim is to define the open questions in this field that are beginning to be elucidated thanks to the advent of mouse models of altered TH metabolism and to obtain novel insights into the physiopathological consequences of TH metabolism on the skin.

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The Thyroid Hormone Inactivator Enzyme, Type 3 Deiodinase, Is Essential for Coordination of Keratinocyte Growth and Differentiation

Cited by 17 publications

References 47 publications

Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

Thyroid hormone action in epidermal development and homeostasis and its implications in the pathophysiology of the skin

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