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Published on: July 8, 2020
Phosphodiesterase-4 Inhibitors Increase Pigment Cell Proliferation and Melanization in Cultured Melanocytes and
Nathaniel B Goldstein1, Zachary B K Berk1, Landon C Tomb1
1Department of Dermatology, University of Colorado, Aurora, Colorado, USA.
Abstract:
Vitiligo is a common chronic autoimmune disease characterized by white macules and patches of the skin, having a negative impact on patients' life and without any definitive cure at present. Identification of new compounds to reverse depigmentation is therefore a pressing need for this disease. The pharmacologic compounds phosphodiesterase-4 inhibitors (PDE4is) are small molecules with immunomodulatory properties used for treatment of inflammatory dermatoses. PDE4is have shown repigmentation effects in patients with vitiligo, in some case reports. We characterized the proliferative and melanogenic potential of 2 known PDE4is-crisaborole and roflumilast-and of a more recently designed compound, PF-07038124. We used 2 in vitro model systems-the primary human melanocyte culture and a 3-dimensional cocultured skin model (MelanoDerm)-with an exploratory testing platform composed of complementary assays (spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, RT-qPCR, western blot, and whole-transcriptome RNA sequencing). We identified that treatment with PDE4is was associated with increased melanocyte proliferation and melanization in both in vitro models and with increase in the melanogenic genes and proteins expression in cultured melanocytes. These effects were found to be enhanced by addition of α-melanocyte-stimulating hormone. Our findings support the further evaluation of PDE4is with or without α-melanocyte-stimulating hormone agonists in vitiligo trials.
Insights
Phosphodiesterase-4 inhibitors (PDE4is) show potential for vitiligo treatment by increasing melanocyte proliferation and melanin production. These compounds, along with alpha-melanocyte-stimulating hormone, may offer new therapeutic avenues for repigmentation.
Area of Science:
- Dermatology
- Immunology
- Pharmacology
Background:
- Vitiligo is a chronic autoimmune skin condition causing depigmentation with significant impact on quality of life.
- Current treatments for vitiligo lack definitive efficacy, highlighting the need for novel therapeutic compounds.
- Phosphodiesterase-4 inhibitors (PDE4is) are known for their immunomodulatory properties and have shown promise in treating inflammatory dermatoses.
Purpose of the Study:
- To investigate the potential of known and novel phosphodiesterase-4 inhibitors (PDE4is) in promoting melanocyte proliferation and melanization.
- To evaluate the effects of PDE4is on melanogenesis-related gene and protein expression.
- To explore the synergistic effects of PDE4is with alpha-melanocyte-stimulating hormone (α-MSH) in vitiligo models.
Main Methods:
- Utilized two in vitro models: primary human melanocyte cultures and a 3D cocultured skin model (MelanoDerm).
- Employed a comprehensive testing platform including spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, RT-qPCR, Western blot, and whole-transcriptome RNA sequencing.
- Characterized the proliferative and melanogenic potential of crisaborole, roflumilast, and PF-07038124.
Main Results:
- Treatment with PDE4is significantly increased melanocyte proliferation and melanization in both in vitro models.
- PDE4is treatment led to increased expression of melanogenic genes and proteins in cultured melanocytes.
- The observed effects of PDE4is were further enhanced by the addition of alpha-melanocyte-stimulating hormone (α-MSH).
Conclusions:
- PDE4is demonstrate significant potential to reverse depigmentation in vitiligo by stimulating melanocyte activity.
- The combination of PDE4is with α-MSH may offer an enhanced therapeutic strategy for vitiligo.
- Further clinical evaluation of PDE4is, with or without α-MSH agonists, is warranted for vitiligo treatment.
