Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo

Schallereuter, Karin U.; Wood, John M.; Ziegler, Irmgard; Lemke, K Regina; Pittelkow, Mark R.; Lindsey, N. J.; Gütlich, Markus

doi:10.1016/0925-4439(94)90027-2

Cited by 153 publications

(127 citation statements)

References 26 publications

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“…Since beta2AR-stimulation activates melanogenesis in vitro, it is tempting to propose that blockade of beta2AR on melanocytes in vivo may contribute to the decrease in melanin synthesis seen in vitiliginous skin. Second, patients with vitiligo exhibit increased plasma and urine concentrations of norepinephrine and its degradation products [57][58][59]. One possible source may be from the keratinocytes within the vitiliginous areas, that have increased levels of 6BH4 [58,60] (Figure 2).…”

Section: Vitiligo and Beta2armentioning

confidence: 99%

“…Second, patients with vitiligo exhibit increased plasma and urine concentrations of norepinephrine and its degradation products [57][58][59]. One possible source may be from the keratinocytes within the vitiliginous areas, that have increased levels of 6BH4 [58,60] (Figure 2). This defect, along with a concomitantly noted reduction in the activity of PNMT, in keratinocytes in affected vitiliginous epidermis [58] (Figure 2) may explain, in part, the accumulation of norepinephrine.…”

Section: Vitiligo and Beta2armentioning

confidence: 99%

“…One possible source may be from the keratinocytes within the vitiliginous areas, that have increased levels of 6BH4 [58,60] (Figure 2). This defect, along with a concomitantly noted reduction in the activity of PNMT, in keratinocytes in affected vitiliginous epidermis [58] (Figure 2) may explain, in part, the accumulation of norepinephrine. Third, epidermal keratinocytes derived from the affected skin of patients with vitiligo (and not the clinically normal appearing skin in these patients), demonstrate increased expression of the beta2AR in culture [12].…”

Section: Vitiligo and Beta2armentioning

confidence: 99%

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Beta Adrenergic Receptors in Keratinocytes

Sivamani

Lam

Isseroff

2007

Dermatologic Clinics

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SynopsisBeta2 adrenergic receptors were identified in keratinocytes more than 30 years ago, but their function in the epidermis continues to be elucidated. Abnormalities in their expression, signaling pathway, or in the generation of endogenous catecholamine agonists by keratinocytes have been implicated in the pathogenesis of cutaneous diseases such as atopic dermatitis, vitiligo and psoriasis. New studies also indicate that the beta2AR also modulates keratinocyte migration, and thus can function to regulate wound re-epithelialization. This review focuses on the function of these receptors in keratinocytes and their contribution to cutaneous physiology and disease.Keywords beta-adrenergic; keratinocyte; atopic dermatitis; psoriasis; vitiligo; wound Physiology of the beta2 adrenergic receptor in keratinocytesOf the several identified classes of adrenergic receptors (alpha and beta, and their subtypes), it is of particular interest to note that human keratinocytes, the cells the make up the majority of the epidermis, express only beta2 adrenergic receptors (beta2AR) [1][2][3][4]. The beta adrenergic receptor is a classic seven transmembrane G protein coupled receptor. These receptors serve as the endogenous receptor to the catecholamine hormones norepinephrine and epinephrine, and can be further subdivided into beta1, beta2, and beta3 subtypes, based on their differential pharmacological response to catecholamines and specific antagonists, as well as differences in their protein sequences [5][6][7].The first studies to suggest the presence of betaAR in the epidermis were functional ones that demonstrated an increase in levels of cAMP in keratinocytes after stimulation with non-specific betaAR agonists [8,9]. Subsequently, work using agonists and antagonists with specificity for the different adrenergic receptor subtypes demonstrated that the increase in keratinocyte

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Section: Vitiligo and Beta2armentioning

confidence: 99%

Section: Vitiligo and Beta2armentioning

confidence: 99%

Section: Vitiligo and Beta2armentioning

confidence: 99%

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Beta Adrenergic Receptors in Keratinocytes

Sivamani

Lam

Isseroff

2007

Dermatologic Clinics

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“…According to Schallreuter's biochemical theory, excessive de novo synthesis of (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4), the essential co-factor of tyrosine hydroxylase which catalyses the first step of the biosynthesis of catecholamines, is a key factor (49). As concerns the relevance to the cause of the disease, the concentration of catecholamines found in vitiligo skin is not considered sufficient to kill melanocytes, and the time course of the production of catecholamines favors a consequence rather than a causal factor (45).…”

Section: Melanocyte Destructionmentioning

confidence: 99%

A Critical Appraisal of Vitiligo Etiologic Theories. Is Melanocyte Loss a Melanocytorrhagy?

Gauthier

andre

Taı̈eb

2003

Pigment Cell Research

264

211

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Common generalized vitiligo is an acquired depigmenting disorder characterized by a chronic and progressive loss of melanocytes from the epidermis and follicular reservoir. However, the mechanism of melanocyte disappearance has never been clearly understood, and the intervention of cellular and humoral autoimmune phenomena as primary events remains unproven. In this review, is discussed the data supporting the major theories of vitiligo, namely melanocyte destruction (autoimmune, neural and impaired redox status) and melanocyte inhibition or defective adhesion. Based on recent morphologic findings in vivo supporting a chronic detachment and transepidermal loss of melanocytes in common generalized vitiligo, a new theory is suggested proposing melanocytorrhagy as the primary defect underlying melanocyte loss, integrating most of the possible triggering/precipitating/ enhancing effects of other known factors.

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“…1 Characterized by patchy depigmentation of the skin, the disease can affect the patients' self-image, or even cause depression, thus substantially decreasing life quality among vitiligo patients. 2 Although several etiological theories, including genetic predisposition, [3][4][5] autoimmunity, 6,7 melanocytorrhagy 8,9 and toxic metabolites 10 have been proposed to participate in the pathogenesis of vitiligo, the exact mechanism of melanocyte degeneration in depigmented lesions still remains unclear.…”

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confidence: 99%

Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

et al. 2015

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Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H 2 O 2 -induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo. Vitiligo is a disfiguring dermatosis with an incidence rate of approximately 0.5-1.0% in the populations worldwide. 1 Characterized by patchy depigmentation of the skin, the disease can affect the patients' self-image, or even cause depression, thus substantially decreasing life quality among vitiligo patients. 2 Although several etiological theories, including genetic predisposition, 3-5 autoimmunity, 6,7 melanocytorrhagy 8,9 and toxic metabolites 10 have been proposed to participate in the pathogenesis of vitiligo, the exact mechanism of melanocyte degeneration in depigmented lesions still remains unclear.The generation of oxidative stress has long been demonstrated to have a crucial role in the onset and progression of vitiligo. 11,12 Owing to the pro-oxidant state generated during melanin synthesis, melanocytes are particularly vulnerable to oxidative stress. 13 In vitiligo, accumulation of toxic intermediates such as 6-and 7-BH4 and catecholamine, 14,15 concomitant with reduced levels and activity of catalase and several other antioxidant enzymes [16][17][18] have been demonstrated in patients' epidermis. Because of these intracellular metabolic disorder and compromised intrinsic antioxidant defenses, hydrogen peroxide (H 2 O ...

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Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo

Cited by 153 publications

References 26 publications

Beta Adrenergic Receptors in Keratinocytes

Beta Adrenergic Receptors in Keratinocytes

A Critical Appraisal of Vitiligo Etiologic Theories. Is Melanocyte Loss a Melanocytorrhagy?

Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

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