What is Melasma?
Melasma, also known as chloasma, is a chronic pigmentary disorder that predominantly affects women of reproductive age, particularly those with darker skin phototypes. It is clinically characterized by symmetrical, brownish macules and patches, typically located on the face, décolletage, and upper arms. Although the precise pathogenesis of melasma remains incompletely explained, ultraviolet (UV) radiation, genetic predisposition, and certain medications are considered key contributing factors. In recent years, increasing attention has been directed toward elucidating the molecular mechanisms underlying melasma, paving the way for the development of novel therapeutic strategies.
Molecular Pathogenesis of Melasma and the Wnt/β-Catenin Signaling Pathway
Melasma is a complex, multifactorial condition involving hyperactivation of melanocytes and functional alterations in both epidermal keratinocytes and dermal fibroblasts. Accumulating evidence implicates aberrant activation of the Wnt/β-catenin signaling pathway as a central mechanism in melasma pathophysiology. This pathway is a pivotal regulator of melanogenesis, maintaining melanocyte homeostasis under physiological conditions. However, its overactivation leads to increased melanin synthesis. In melasma-affected skin, elevated expression of Wnt ligands and nuclear β-catenin has been observed, suggesting their direct involvement in the disease process. Hyperactivation of Wnt/β-catenin signaling upregulates the expression of Microphthalmia-associated Transcription Factor (MITF), the master regulator of melanocyte differentiation and melanin production.
Figure 1. The Wnt/β-Catenin Pathway. In an inactive state β-catenin is degraded by the APC/Axin/CK1/GSK-3β destruction complex and subsequently degraded in the cytoplasm, preventing gene transcription. Upon Wnt activation, Wnt ligands bind to the Fz/LRP5/6 receptor complex, leading to the recruitment of Axin to phosphorylated Dvl, inhibition of GSK-3β activity, and stabilization of β-catenin. Stabilized β-catenin then translocates to the nucleus, where it activates TCF/LEF-mediated target gene expression.
The Role of DKK1 in Melasma
The Wnt/β-catenin pathway is tightly regulated by a network of modulators, including both activators and inhibitors. One of the key endogenous inhibitors is Dickkopf-1 (DKK-1), a secreted glycoprotein involved in the suppression of melanogenic activity. In healthy skin, keratinocytes exhibit high expression of DKK-1, which restrains melanocyte activation and prevents hyperpigmentation. In contrast, melasma lesions show markedly reduced DKK-1 levels, leading to dysregulated Wnt signaling and increased melanin synthesis. This discovery highlights the therapeutic potential of targeting DKK-1 expression as a molecular intervention in melasma.
Current Therapeutic Strategies in Melasma Management
A variety of treatment modalities are currently employed in esthetic and dermatological practice to manage hyperpigmentation. These include fractional laser therapies, chemical peels, and the application of topical agents with depigmenting properties. Another promising approach is mesotherapy using antioxidants and depigmenting compounds, which allows for targeted delivery of active substances into the dermis, facilitating pigment reduction and skin restoration.
One of the most innovative and promising strategies is the use of activated platelet-rich plasma enriched with DKK-1 (DKK-PRP). DKK-1, as a natural inhibitor of the Wnt/β-catenin pathway, plays a crucial role in regulating melanogenesis. DKK-PRP may more effectively suppress melanocyte activity, thereby reducing pigmentation and improving skin tone. Conventional PRP, owing to its high concentration of growth factors, has anti-inflammatory and regenerative properties that can modulate melanocyte behavior. Clinical studies indicate that PRP may attenuate hyperpigmentation by reducing inflammation and downregulating MITF expression. Upon activation, platelet-rich plasma induces DKK-1 secretion, offering a novel, targeted mechanism of action. This makes DKK-PRP a potentially groundbreaking advancement in melasma therapy.
Given its multifactorial etiology and tendency for recurrence, melasma remains a significant clinical challenge. However, advancing our understanding of its molecular underpinnings provides a foundation for more effective and durable treatment options.