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

Abstract

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.

Keywords: Deiodinases; Epithelial homeostasis; Skin physiology; Thyroid hormone metabolism; Thyroid hormones.

Fig. 1

Anatomy of the skin and thyroid hormone signal. a The structure of the skin reflects the complexity of its functions. It is characterized by two main components, the epidermis and the dermis, which are separated by a basement membrane. The outermost level, the epidermis, is a stratified squamous epithelium, that consists of a specific constellation of cells known as “keratinocytes”, which function to synthesize keratin. The epidermis is composed of several cell layers (from inside to outside): basal layer (BL), spinous layer (SL), granular layer (GL), stratum lucidum (SL) and stratum corneum (SC). b The TH signal is regulated in the skin by the transport of T3 and T4 across the plasma membrane and the enzymatic activation or inactivation catalyzed by D2 and D3. Finally, the binding of T3 to TRs regulates the expression of responsive genes in the keratinocytes K5, K6, K14, K15 and K16, which confirms that TH is a key endocrine regulator that affects keratinocyte proliferation and differentiation

Fig. 2

Schematic description of mouse models of TH signal alteration in the skin. TRKO mice show defective proliferation of keratinocytes in both physiological and pathological conditions. sD3KO mice show reduced proliferation and enhanced differentiation of keratinocytes and enhanced tumor invasiveness. Conversely, sD2KO mice display fasting growing Squamous Cell Carcinoma (SCC) tumors with low metastatic propensity