Therapeutic Implications of the Circadian Clock on Skin Function

February 2014 | Volume 13 | Issue 2 | Original Article | 130 | Copyright © 2014

Adam J. Luber BA, Shaheen H. Ensanyat BS, and Joshua A. Zeichner MD

Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, NY

Abstract

The human circadian clock ensures that biochemical and physiological processes occur at the optimal time of day. In addition to a central pacemaker in the body, recent evidence suggests that peripheral mammalian tissues also possess autonomous circadian oscillators, which are regulated by genes linked to distinct tissue-specific functions. The skin is situated in a position naturally exposed to diurnal environmental changes. The skin's chronobiological functioning influences skin aging, cell repair and development of skin cancers, as well as optimal timing of drug delivery to the skin. An understanding of circadian skin-related functions and the impact of their disruption allow clinicians to improve therapeutic decision-making and maximize the effectiveness of prescribed treatments.

J Drugs Dermatol. 2014;13(2):130-134.

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INTRODUCTION

Our circadian rhythm is an endogenous timing system generated from the body’s central pacemaker, the suprachiasmatic nucleus (SCN). Located in the hypothalamus and superior to the optic chiasm, its position optimizes its ability to monitor light and darkness. The SCN exhibits oscillations approximately every 24 hours and coordinates specific physiologic and biochemical processes to occur at the optimal time of day. The primary chronobiological functions of the SCN are to control core body temperature and mitotic gene expression, thereby regulating cell differentiation and proliferation. Animal models demonstrate increased mitotic activity during the late night and early morning hours, a time designated for growth and repair.1,2

While the body has a central circadian clock, specific organs, such as the skin, contain peripheral circadian oscillators that regulate local processes. Peripheral oscillators are composed of specific proteins with regulated expression patterns throughout the day.2–6 With tight regulation of time-sensitive genes, signals generated by the SCN are amplified at the level of the specific peripheral tissue.7–9

Molecular Mechanisms

Skin functions are influenced by clock genes, which generate proteins that work in a complex network of molecular feedback loops to generate circadian patterns of cellular functions.10 The expression of these genes has been studied in vitro in cultured human skin cells, including keratinocytes, melanocytes, and dermal fibroblasts.11 The clock genes Bmal1, Per1, and Cry1 also demonstrated circadian rhythms in vivo in human skin biopsies. 12 Each of the different types of skin cells contain distinct circadian clock machinery that autonomously drives its particular skin functions.10 Recently, Krüppel-like factor 9 (Klf9) has been identified as a circadian transcription factor in human epidermis that regulates keratinocyte proliferation by controlling the expression of target genes in a daytime-dependent manner.9

Circadian Rhythms in the Skin

The skin is uniquely positioned at the interface between body and external environment. As such, it is naturally exposed to diurnal changes in the environment, including temperature, light, humidity, UV radiation, and pathogens. Regulated circadian activities allow the skin to adapt its daily functions to variations in environmental conditions.10 Predictable daily periodicity has been reported in skin cell proliferation rates, hydration and transepidermal water loss (TEWL), capillary blood flow, sebum production, temperature, surface pH, and appearance of rhytides in humans.9,10,13–18

Both humans and animals exhibit diurnal variations in mitotic activity. In animal models, mitoses have been shown to be lightresponsive, with active cell division occurring preferentially in the late night to early morning.1 Human epidermal cells also divide and proliferate in a finely-timed circadian manner.17 DNA synthesis (cell cycle S-phase) peaks at roughly 3:30 PM, while mitosis (M-phase) peaks at approximately 11:30 PM. Thus, cell growth and repair occur mainly in the evening.17 This knowledge can be correlated clinically, with strategic scheduling of drug delivery to take advantage of differences in cell proliferation rates throughout the day.17

Skin hydration depends on many factors, including skin permeability and the amount of water lost across the epidermis. Transepidermal water loss (TEWL) is significantly higher in

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