Biomolecular aspects of hyperpigmentation disorders
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This document outlines topics related to hyperpigmentation, including the synthesis of melanin, transport of melanosomes, and a focus on melasma. It lists several references on these topics, such as papers on melanosome membrane dynamics, heterogeneity of melanocytes, and recent progress in understanding melasma pathogenesis.
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Biomolecular aspects of hyperpigmentation disorders
- 1. UNDERSTANDING BIOMOLECULAR ASPECTS OF HYPERPIGMENTATION Peter Nugraha Soekmadji Department of Dermatovenereology Faculty of Medicine Maranatha Christian University Bandung
- 2. TOPICS OUTLINE 1. Synthesis of melanin 2. Transport of melanosome 3. Focus on melasma
- 4. David G. Greenhalgh. A Primer on Pigmentation. J Burn Care Res 2015;36:247–257
- 5. Miroslawa Cichorek, Malgorzata Wachulska, Aneta Stasiewicz. Heterogeneity of neural crest-derived melanocytes. Cent. Eur. J. Biol. 8(4) 2013. 315-330 DOI: 10.2478/s11535-013-0141-1
- 6. Fitzpatrick's Dermatology in General Medicine, 8th Edition
- 7. David G. Greenhalgh. A Primer on Pigmentation. J Burn Care Res 2015;36:247–257
- 8. Miroslawa Cichorek, Malgorzata Wachulska, Aneta Stasiewicz. Heterogeneity of neural crest-derived melanocytes. Cent. Eur. J. Biol. 8(4) 2013. 315-330 DOI: 10.2478/s11535-013-0141-1
- 10. Michael S. Marks and Miguel C. Seabra. The melanosome: membrane dynamics in black and white. Mol Cell Bio 2001 Oct
- 11. Michael S. Marks and Miguel C. Seabra. The melanosome: membrane dynamics in black and white. Mol Cell Bio 2001 Oct
- 15. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 16. Soon-Hyo Kwon, Young-Ji Hwang, Soo-Keun Lee and Kyoung-Chan Park. Heterogeneous Pathology of Melasma and Its Clinical Implications. Int. J. Mol. Sci. 2016, 17, 824; doi:10.3390/ijms17060824
- 17. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 18. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 19. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 20. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 21. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 22. Ai-Young Lee. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res.28; 648–660
- 23. Ai-Young Lee. An updated review of melasma pathogenesis. DERMATOLOGICA SINICA 32 (2014) 233e239
Editor's Notes
- Melanocytes (yellow) exist in the basal (bottom) layer of the epidermis and have multiple dendrites that transfer melanosomes to sites above the nucleus of keratinocytes (grey) to protect their DNA from UV light.
- Melanocytes localization in the epidermis and hair. The epidermal melanocytes are located among the basal layer (stratum basalis) of a stratified squamos keratinized epithelium (A). The hair melanocytes are between cells covering the hair papilla in the hair bulb (B). Stem cells for melanocytes are located in the region named the hair bulge
- The biochemical and cellular pathways of melanosome production in response to UV light. Ultraviolet (UV) light exposure to a keratinocyte that overcomes the protection of melanosomes (brown/black ovals) leads to DNA stress. Sunscreen and protective clothing inhibit this reaction. DNA stress leads to proteins, such as p53, that assist with DNA repair and, at the same time, lead to production of proopiomelanocortin (POMC). POMC is the precursor of α-MSH, which is secreted from the keratinocyte and binds to its receptor (MC1R). MC1R activation increases adenyl cyclase to produce cAMP. Epinephrine binding to the β-adrenergic receptor (betaAR) also increases adenyl cyclase activity, whereas UV light activates bone matrix protein receptors to inhibit the activation. Many other cytokines (described in the text) influence the activity of melanin synthesis. cAMP activity is prolonged by inhibiting its breakdown through phosphodiesterase 4D3 inhibitors (PDEI4). cAMP then activates protein kinase A (PKA) to phosphorylate CREB, which then binds to the CREB responsive element (CRE) to produce the main activator or melanin production (MITF). Signaling through steel factorwhich binds to the receptor cKIT produces MAP kinases that in turn phosphorylate MITF to produce tyrosinase (TYR), TYRP1 (or DCT), and TYRP2. Tyrosinase is the rate-limiting enzyme for converting tyrosine to DOPA and DOPAquinone. Dopaquinone can either take on cysteines to lead to the red pigment pheomelaninor with the use of TYRP2 and TYRP1 produce the brown/black pigment eumelanin. Melanosomes start off as empty lysosome-like structures (stage 1) that pick up either pigment at stage 2. The pigments are then concentrated into stage 3 and stage 4 melanosomes as they travel up actin filaments with the assistance of kinesin/myosin motors to the tip of dendrites. The keratinocyte has special receptors called protease-activated receptor-2 (PAR2) that accept the melanosomes. The melanosomes are then transferred to the keratinocyte by processes resembling phagocytosis. Once in the keratinocyte, the melanosomes are transferred to above the nucleus to provide more protection from UV light—leading to a tan
- The graphical presentation of the basic cross-talk between melanocytes and keratinocytes in the epidermis. The melanocytes proliferation, differentiation, melanogenesis are under control of surrounding keratinocytes. Melanocyte and up to 40 keratinocytes form the epidermal melanin unit. CF stem cell factor; bFGF basic fibroblast growth factor; GM-CSF granulocyte-macrophage colonystimulating factor; ET-1 endothelin 1; a-MSH melanocyte-stimulating hormones; PGE2 prostaglandin E2; PGF2aprostaglandin F2a; NGF nerve growth factor; c-Kit tyrosine kinase receptor; FGFR1/2 fibroblast growth factor receptor; GM-CSFR granulocytemacrophage colony-stimulating factor receptor; ETBR endothelin B receptor; MC1R melanocortin 1 receptor; EP1/EP3/FP prostanoid receptors; NGFR nerve growth factor receptor; MAPK mitogen-activated protein (MAP) kinases ; PKC Protein kinase C; PKA Protein kinase A; PLC phospholipase C; TYR tyrosinase; TRP1 tyrosinase-related protein 1; TRP2 tyrosinase-related protein 2; MITF-M Melanocyte-specific MITF (Microphthalmia-associated transcription factor) isoform; CRE cAMP response elements; CREB cAMP response element-binding.
- Melanosome maturation. a| Schematic diagram of a portion of the cell body and dendrite of a skin melanocyte, with stage I, II, III and IV melanosomes and other relevant organelles indicated. The degree of melanization is indicated by black. Vesicles budding from the trans-Golgi network contain tyrosinase. Stage I premelanosomes probably correspond to the coated endosome described in the text. b| Electron micrograph of a melanocyte, which demonstrates the salient features of stages II, III, and IV melanosomes. Courtesy of L. Collinson and C. Hopkins, Imperial College, London, UK.
- Model of melanosome transport in epidermal melanocytes.Schematic diagram of a portion of the cell body and dendrite of a skin melanocyte. Melanosomes mature in the perinuclear region and bind kinesin, a plus-end-directed microtubule motor. Melanosomes move along microtubules towards the cell periphery. Once at the periphery, melanosomes detach from microtubules and bind actin filaments through the molecular motor, myosin Va. This step retains melanosomes at the periphery of the cell, from where they can be transferred to adjacent keratinocytes.
- Schematic view of melanogenesis induced by external stimuli, particularly UV radiation. Direct effects on melanocytes and indirect effects on keratinocytes/fibroblasts releasing melanogenic factors, such as proopiomelanocortin (POMC)-derived peptides (MSH, ACTH), ET-1, SCF, bFGF, or NGF, are involved in melanogenesis. Protein kinase C (PKC), NO, and cAMP are major intracellular signal transduction pathways. The black ovals indicate melanosomes (DAG, 1,2-diacylglycerol; NO, nitric oxide; MSH, melanocyte-stimulating hormone; ACTH, adrenocorticotrophic hormone; ET-1, endothelin-1; SCF, stem cell factor; bFGF, basic fibroblast growth factor; NGF, nerve growth factor; MC1R, melanocortin-1 receptor; TYR, tyrosinase; TRP, tyrosinase-related protein).
- The role of mast cells in melanogenesis and photoaging. UV= ultraviolet; MMPs = matrix metalloproteases; VEGF = vascular endothelial growth factor; FGF-2 = fibroblast growth factor-2; TGF-β= transforming growth factor-β; ECM = extracellular matrix; BM = basement membrane.
- Factors involved in e melanogenesis in melasma versus other hyperpigmentation disorders. Decreased expression of H19 RNA and WIF-1 is involved in the pathogenesis of melasma, but not post-inflammatory hyperpigmentation and UV-induced pigmentation (WIF-1, Wnt inhibitory factor 1).
- Schematic view of the role of H19-derived miR-675 in keratinocytes in melasma. MiR-675 is delivered from keratinocytes to melanocytes and fibroblasts via membranebound exosomes. MiR-675 could exert the action through either microphthalmiaassociated transcription factor (MITF) in melanocytes or CDH11 in fibroblasts/keratinocytes as its target. CDH11 in fibroblasts or keratinocytes is involved in melanogenesis via the canonical Wnt and AKT activation pathways in neighboring melanocytes through the induction of Ncadherin (CDH, cadherin; AKT, apoptosis signal-regulating kinase; TYR, tyrosinase; TRP, tyrosinase-related protein).
- Role of WIF-1 in fibroblasts (or keratinocytes) in melanogenesis. Reduced WIF-1 expression in fibroblasts (or keratinocytes) increases Wnt expression and action in melanocytes through the canonical Wnt/beta-catenin pathway with microphthalmia-associated transcription factor (MITF) upregulation and the non-canonical pathway with NFATc2 translocation to nucleus (WIF-1, Wnt inhibitory factor 1; LEF-1, lymphocyte enhancer binding factor 1; NFAT, nuclear factor of activated T cells).
- Mechanism involved in estrogen-induced melanogenesis and PDZK1 role in melasma. (A) By binding to ERs, estrogen enhances cAMP levels and upregulates CREB, MITF, and tyrosinase family protein expression, with the involvement of the PKA pathway. (B) PDZK1 could facilitate the estrogen action by interaction with other proteins including ion exchangers, resulting in the stimulation of melanogenesis and melanosome transfer in melasma patients (ER, estrogen receptor; PKA, protein kinase A; CREB, cAMP responsive-element-binding protein; CBP, CREB-binding protein; MITF, micropthalmia-associated transcription factor; TYR, tyrosinase; TRP, tyrosinase-related protein; PDZK1, PDZ domain protein kidney 1; NHE, sodium–hydrogen exchanger; CFTR, cystic fibrosis transmembrane conductance regulator).
- A schematic view of the role of triggering factors in melasma development: increased expression of NGF receptor with NGF and alpha-MSH with MC1R; PDZK1 upregulation in both melanocytes and keratinocytes; increased SCF from dermalfibroblasts; reduced WIF-1 in dermalfibroblasts as well as epidermal keratinocytes; reduced H19 in keratinocytes are involved in stimulation of melanogenesis and melanosome transfer in hyperpigmented lesional skin compared to normally pigmented skin of melasma patients. miR-675, a microRNA of H19 RNA, is released from keratinocytes as exosomes, and delivered to neighboring melanocytes orfibroblasts, regulating pigmentation via a direct target, such as MITF. miR-675 inhibits melanogenesis by targeting MITF. The melanogenic response of each skin cell type (melanocytes, keratinocytes, fibroblasts) and cell-to-cell interaction in response to UV exposure, female sex hormones, and stress could be different in different individuals. cAMP ¼3 0,50-cyclic adenosine monophosphate; MAPK¼mitogen-activated protein kinase; MC1R¼melanocortin-1 receptor; MITF¼microphthalmia-associated transcription factor; MSH¼melanocyte stimulating hormone; NGF¼nerve growth factor; PAR-2¼protease-activated receptor-2; PDZK1¼PDZ domain containing 1; PKA¼protein kinase A; PKC¼protein kinase C; SCF¼stem cell factor; UVR¼UV radiation; WIF-1¼Wnt inhibitory factor-1.