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Beni-Suef University Journal of Basic and Applied Sciences
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Clinical study of Wnt inhibitory factor-1 expression and its association with disease severity in non-segmental vitiligo

Beni-Suef University Journal of Basic and Applied Sciences volume 13, Article number: 89 (2024) Cite this article

Abstract

Background

Vitiligo is classified as an acquired chronic depigmentation disorder that includes the destruction of epidermal melanocytes. It affects 0.5–1% of the population all over the world. Wnt signaling pathway is vital in melanocytes differentiation and development. WIF-1 is an antagonist of the Wnt signaling pathway; it hinders Wnt from binding its receptors. The present study aims to detect WIF-1 expression in vitiligo skin and if it relates to the disease's severity.

Results

This case–control study included 70 subjects: 35 vitiligo patients and 35 healthy controls. Skin WIF-1 expression was estimated using quantitative real-time PCR. Assessment of the vitiligo disease activity score and vitiligo area severity index score was determined. WIF-1 expression showed significant elevation in the skin of vitiligo patients compared to the healthy control group.

Conclusion

Overexpression of WIF-1 may participate in the pathogenesis of vitiligo; hence, it should be a future therapeutic target.

1 Background

Vitiligo is a chronic acquired depigmentation disorder, one of its unique characteristics is the destruction of melanocytes in the epidermis [1,2,3]. About 0.5–1% of the population in the world is affected by vitiligo [4, 5]. Nearly 50% of the patients had a presentation of the disease below 20 years [6, 7]. Additionally, it can cause major psychological disturbance and low quality of life, as in most cases, the face and other visible body parts [8,9,10]. It is still unclear why vitiligo occurs, despite multiple theories that tried to explain the pathogenesis of the disorder; genetic susceptibility [11], immune disturbances [12, 13], melanocytorrhagy [14], and abnormal metabolism [15].

If there is a susceptive genetic background, autoimmune destruction of melanocytes will occur causing the functional melanocytes to be lost from the epidermis leading to the known depigmentation on the skin. Autoreactive CD8+ T cells participate in the destruction of melanocytes [16, 17]; however, the initial event in this destruction may be oxidative stress (OS) [18].

The Wnt signaling pathway is a conserved pathway that participates pivotally in several biological processes, such as the adults' tissue regeneration [19]. It is composed of two main pathways: the canonical and non-canonical. Another name of the canonical pathway is the Wnt/β-catenin pathway, while the two non-canonical pathways are the Wnt/planar cell polarity and the Wnt/calcium pathways [20]. Responsibilities of the Wnt signaling pathway include control of multiple intracellular signaling pathways, which are important for embryogenic development, cellular differentiation, migration, and stem cell biology control [21].

The Wnt signaling pathway presents a prominent role in the differentiation of melanocyte stem cells [22, 23], enhances neural crest cell differentiation into melanocytes [24, 25], and promotes the proliferation and differentiation of melanocytes [26]. Furthermore, Wnt/β-catenin signaling participates crucially in proliferation, migration, and differentiation in the pigmentation systems of skin [27].

Recent combined analyses of three vitiligo microarrays showed that the Wnt signaling pathway was downregulated. These analyses also revealed that the Wnt signaling pathway was differentially expressed between lesional and non-lesional skin of vitiligo patients. It was characterized as a major pathway in the pathogenesis of vitiligo [28]. Transcriptome analysis also demonstrated that the Wnt/β-catenin pathway was downregulated in the lesional skin of vitiligo patients. In lesional vitiligo skin, there is a notably decreased expression of lymphoid enhancer-binding factor 1 (LEF1), which is a marker of Wnt signaling pathway activation [29].

These results suggest that the downregulation of the Wnt signaling pathway has a vital role in the pathogenesis of vitiligo, and its upregulation may be effective in the therapeutic approach to vitiligo.

The treatment of vitiligo has two main steps. The first aims to control the exaggerated immune response and arrest the active disease progression. The second step is repigmentation of the depigmented patches [16].

As regards the first step of vitiligo treatment (controlling the autoimmune response to arrest the progression of the disease activity), this can be achieved through multiple mechanisms: (1) protecting melanocytes from OS damage [30], (2) inhibiting differentiation of CD8 + T cells into effector cells [31], and (3) enhancing regulatory T cells (Tregs) [32]. These previously mentioned mechanisms could be enhanced by the Wnt signaling pathway [33].

The second step of vitiligo treatment is repigmentation of the diseased patches. To successfully achieve repigmentation, the lost melanocytes should be compensated through melanocyte regeneration [33]. Wnt signaling pathway has prominent participation in the repigmentation process; (1) Wnt signaling pathway is activated in hair follicle melanocyte stem cells (McSCs) and in other precursors of melanocytes, which enhances differentiation of melanocytes and promotes their regeneration [33], and (2) it also has been shown to promote melanogenesis in melanocytes, through various factors as melanocyte-inducing transcription factor (MITF); which acts as a regulator of melanogenesis. These result in epidermal repigmentation [34, 35].

Several Wnt antagonists were investigated and were shown to be highly expressed in vitiligo patients suppressing the Wnt/β-catenin signaling pathway; secreted frizzled-related proteins (sFRPs) [36], Dickkopf-related protein 1 (DKK1) [37], and tumor protein P53 (p53) [38].

One of the Wnt signaling pathway antagonists is WIF-1; Wnt inhibitory factor-1. It can bind to Wnt ligands, inhibiting the Wnt signaling pathway [39]. However, WIF-1 expression in vitiligo skin patients has not been sufficiently investigated. Hence, we speculated that WIF-1 might participate in the pathogenesis of vitiligo by downregulating the Wnt signaling pathway.

Therefore, this study aimed to assess WIF-1 expression in vitiligo patients and compare these to normal healthy controls. We also aimed to study patients’ WIF-1 expression concerning their demographic and clinical characteristics, including disease severity scores (VIDA and VASI) to check the possibility of using WIF-1 as a disease activity marker, hoping to pave the way for new therapeutic modalities for vitiligo that target Wnt signaling pathway.

2 Methods

2.1 Study population

The current study is a case–control with 70 adults: 35 vitiligo patients and 35 healthy controls. Both have the same ethnicity, gender, and age which were similar in both groups. After local ethical committee approval, we explained the research details to all the participants in the study, and then, we obtained their informed consent before sample collection. Enrollment roles of this research included the ages between 20 and 60 years and the diagnosis of vitiligo without receiving any treatment except topical emollients for 1 month before the study. Below 20 years and above 60 years were the excluded age groups. Additionally, this research excluded the individuals who are pregnant or lactating females, patients suffering from other autoimmune diseases or other hypopigmentation disorders, those who received systemic steroids during the last month before sampling, and patients on phototherapy.

2.2 Clinical measurements

Depending on history, clinical examination, and using Woods's lamp, the vitiligo was diagnosed. Clinical findings and assessment of the vitiligo disease activity (VIDA) score [40] and the vitiligo area severity index (VASI) score [41] were determined by the attending dermatologist.

2.3 Sample collection and processing

A 4-mm sample of punch skin biopsy was obtained from the two groups and stored at − 80 °C until the real-time PCR for WIF-1 expression analysis.

For vitiligo patients, the biopsy was obtained from (1) the margin of active vitiligo lesions (non-exposed sites), which was determined through the history of the disease progression or old lesions extension, and also through using Wood’s light to define the actual margin, or from (2) the margin of the latest lesion. For healthy controls, the biopsy sites were defined as vis-a-vis areas of the vitiliginous patches of the patients.

2.4 WIF-1 expression analysis

WIF-1 expression was analyzed using the technique of real-time PCR. The supplier of the WIF-1 extraction kit was mirVanaTM PARISTM Kit, Ambion, USA. A Qiagen kit (Qiagen, USA) was used to isolate total RNA. Then, we studied the primer database with the following sequences:

2.5 Primers of WIF-1

Forward primer: 5′-CCGAAATGGAGGCTTTTGTA-3;

Reverse primer: 5′-TGGTTGAGCAGTTTGCTTTG-3′

And β-actin:

Forward primer: 5′-ATCACCATCTTCCAGGAGCG-3′;

Reverse primer: 5′-CCTGCTTCACCACCTTCTTG-3′

Then, we optimized the real-time PCR assay and the primers at the annealing temperature. The relative quantification (RQ)—relative expression—was calculated in accordance with the Applied Biosystem StepOne™ software (version 3.1). We also calculated the fold change results using the PCR threshold cycle (2−ΔΔCT).

2.6 Statistical analysis

We used the means and standard deviation (SD) to present our quantitative data. For comparisons between means of the study groups, we used Student’s t-test, whereas we used the frequencies and percentages to present our qualitative data. For comparisons between the two groups, the Chi-squared (χ2) test was used. Also, odds ratios (ORs) and their 95% confidence intervals (CIs) were tools for comparing both groups. The level of significance was considered at a p-value < 0.05. Statistical analysis was performed using the Statistical Package for the Scientific Studies (SPSS) 16.0 for Windows (SPSS®, Inc., Chicago, IL, USA).

3 Results

3.1 Demographics of the study groups

The demographics of the vitiligo cases and healthy controls are summarized below (Table 1). In both groups, there were thirteen (37.1%) males and twenty-two females (62.9%). Patients’ ages ranged from 18 to 50 years with a mean value of 32.6 ± 11.11, while the age of the controls was from 19 to 52 with an average of 35.5 ± 8.08 years old, with no noticed statistically significant difference as regards age and sex among both groups (p-value > 0.05).

Table 1 Demographics of vitiligo cases and healthy controls
Full size table

3.2 Clinical parameters and characteristics of disease in vitiligo cases

The clinical data of vitiligo patients are illustrated below (Table 2). In vitiligo patients, the most frequent skin type was type IV (23, 65.7%), followed by type III (11, 31.4%) and type V (1, 2.9%). The most common type of vitiligo was vulgaris in 16 patients (45.7%), followed by mixed type in 11 (31.4%), then focal, acral, segmental, and universalis in equal percentages (5.7%). Face affection was noticed in 60.0% of patients, and hands and feet affection was in 65.7%. Most of the studied participants of vitiligo cases had not a family history of vitiligo (29, 82.9%), while only six of them had a positive family history of vitiligo (17.1%). The mean duration of the last new lesions was 5.87 ± 5.8, and the mean percentage of extent was 23.65 ± 22.5. Regarding disease scores, the mean VASI was 20.34 ± 22.2, and the mean VIDA score was 2.34 ± 1.4.

Table 2 Clinical parameters and disease characteristics of vitiligo patients
Full size table

3.3 WIF-1 expression in vitiligo cases and healthy individuals

WIF-1 expression in the study groups is demonstrated (Table 3 and Fig. 1). The mean WIF-1 expression was 4.37 ± 2.35 in vitiligo patients, while it was 1.02 ± 0.02 in healthy controls. WIF-1 expression was significantly increased in the vitiligo cases group than in healthy controls (p < 0.001).

Table 3 Comparison of WIF-1 expression among the studied cases and controls
Full size table
Fig. 1
figure 1

Comparison of WIF-1 expression among the studied vitiligo cases and healthy controls

Full size image

3.4 WIF-1 expression association with clinical data among vitiligo cases

The association of WIF-1 expression with clinical parameters among the studied vitiligo cases revealed no significance, as summarized in Table 4.

Table 4 Association of WIF-1 expression and clinical data among the studied vitiligo cases
Full size table

3.5 Correlation between WIF-1 expression and disease severity

There were non-significant correlations detected (p > 0.05) between WIF1 level and VIDA scores. Also, there were non-significant correlations observed (p > 0.05) between WIF-1 level and VASI scores. The correlation between WIF-1 expression and clinical characteristics is shown in Table 5.

Table 5 Correlation of WIF-1 expression with the clinical characteristics of vitiligo cases
Full size table

4 Discussion

This study revealed the characteristics of 35 vitiligo patients; the mean age was 32.6 years with a standard deviation of 11.11. The minimum age was 18 years, whereas the maximum was 50 years. A percentage of 37.1% of patients were males, and 62.9% were females. The majority of cases (65.71%) had skin type IV, and nearly half (45.7%) were diagnosed as vitiligo vulgaris face, hands, and feet were mostly affected (60.0% and 65.7%, respectively). Mostly, vitiligo patients had a negative family history (82.9%). The mean duration of the last new lesions was 5.87 ± 5.8 months, with a range of 0.25–24.0 months. The mean percentage of extent was 23.65 ± 22.5. The mean VASI score was 20.34 ± 22.2, and the mean VIDA score was 2.34 ± 1.4.

The Wnt signaling pathway participates pivotally in the development process of neural crest-derived melanocytes, in melanocyte differentiation, and it also participates in the melanogenesis of human melanocytes of adults. WIF-1 is one of the modulators of the Wnt signaling pathway, that is expressed by melanocytes [42]; hence, it could be used in vitiligo disease pathogenesis. WIF-1 is a secretory protein that inhibits the activity of the Wnt signaling pathway. WIF-1 can trap soluble Wnt ligands to prevent their interaction with frizzled receptors. It blocks both branches of the Wnt signaling pathway; Wnt/β-catenin and β-catenin-independent [43, 44].

As upregulation of the Wnt signaling pathway contributes to the control of immune response and thereby the protection of melanocytes from oxidative stress, inhibition of CD8 + cytotoxic T lymphocytes, and activation of Tregs [45], its downregulation by WIF-1 in vitiligo patients can induce an autoimmune response causing progression of the disease. Additionally, by inhibiting the Wnt signaling pathway, WIF-1 hinders melanocyte differentiation and regeneration [33], and suppresses melanogenesis in melanocytes, through inhibition of MITF and its downstream melanogenic enzymes [27]. The current study showed that WIF-1 expression in the vitiligo group was significantly higher as compared to the control group.

Our results agreed with Regazzetti et al. (2015); who reported that the Wnt signaling pathway is disturbed in the skin of vitiligo patients; either lesional or non-lesional. Wnt signaling pathway has stimulated the melanocyte precursors differentiation so impaired signaling hinders the proliferation of melanocytes, and negatively affects differentiation into functional melanocytes [29].

Similarly, the study of Zou et al. (2020) revealed that gene expression of one of the Wnt antagonists; secreted frizzled-related protein 5 (SFRP5) expression was significantly increased in the diseased vitiligo melanocytes than in normal epidermal melanocytes in vitiligo patients. Overexpression of SFRP5 suppressed melanogenesis through suppressing the Wnt signaling pathway in melanocytes. They also revealed that SFRP5 silencing helped restore pigmentation in the diseased vitiligo melanocytes via the Wnt signaling pathway [36].

Our work was supported by Goldstein et al. (2016); who assessed the expression values of various gene transcripts of melanocytic stem cells including WIF1; which was higher in the vitiligo group than the normal control [30]. They also concluded that repigmentation in narrow-band UVB (NBUVB)-treated vitiligo has an association with Wnt/β-catenin pathway activation [35].

Additionally, we are in harmony with the data of Kim et al. (2013); who reported that declined expression of WIF-1 in keratinocytes of the epidermis and fibroblasts of the dermis has a key role in melasma pathogenesis through melanogenesis stimulation and melanosome transfer by Wnt signaling pathway upregulation [46]. Despite the uncertainty of the mechanism of affection of melanogenesis in melanocytes by the declined WIF-1 expression in the other nearby cells, Kim et al. (2013) suggested a paracrine effect, because of an unrecognizable expression of WIF-1 in melanocytes; hence, they proposed that declined WIF-1 expression in the other adjacent cells (cells other than melanocytes) may lessen binding of WIF-1 to Wnt molecules in melanocytes, leading to elevated Wnt expression and acting via Wnt signaling pathways [46].

Moreover, the study of Hwang et al. (2013) supported our results. They illustrated that pigmentation suppression—melanin synthesis inhibition—in melanoma cell lines treated with NSC-CM (neural stem cell-conditioned medium) was directly related to Wnt/β-catenin signaling inhibition. This signaling inhibition was demonstrated by the increased expression of Wnt inhibitors, including WIF-1, Dickkopf-1,2,3 (DKK1), SFRP2, and SFRP5 [47].

Our study firstly revealed that WIF-1 is upregulated in patients with vitiligo causing suppression of the Wnt signaling pathway, and the previous studies postulated that restoring the Wnt signaling pathway may participate in the immune response controlling; which is supportive for the first step of vitiligo treatment that aims at controlling the autoimmune response and arresting the progress of active disease [33], and in repigmentation of the depigmented areas; which is the second step of vitiligo treatment [16]. Hence, the development of WIF-1 inhibitors could be a synergetic drug for the currently used immunosuppressive agents to shut down autoimmune responses and enhance melanocyte regeneration in vitiligo patients.

5 Conclusion

Overexpression of WIF-1 may be a key player in vitiligo pathogenesis; thereby, its knocking down should be considered as a future therapeutic target for vitiligo treatment.

Abbreviations

DKK1:

Dickkopf-1

MITF:

Microphthalmia-associated transcription factor

McSCs:

Melanocyte stem cells

NBUVB:

Narrow-band UVB

NSC-CM:

Neural stem cell-conditioned medium

OS:

Oxidative stress

SFRP5:

Secreted frizzled-related protein 5

Tregs:

Regulatory T cells

VASI:

Vitiligo area severity index

VIDA:

Vitiligo disease activity score

WIF-1:

Wnt inhibitory factor-1

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Acknowledgements

Not applicable.

Funding

The study was not funded by any supporting organization.

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Authors and Affiliations

  1. Dermatology and Venerology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt

    Yasser Mostafa Gohary, Aya Nagy Sayed & Hanan Abd El Razik Kamel

  2. Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Beni-Suef University, Mohammed Hassan Street, Beni Suef, 62511, Egypt

    Ebtehal Gamal Abdelhady

  3. Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt

    Laila Ahmed Rashed

Authors
  1. Yasser Mostafa Gohary
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  2. Ebtehal Gamal Abdelhady
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  3. Aya Nagy Sayed
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  4. Laila Ahmed Rashed
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  5. Hanan Abd El Razik Kamel
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Contributions

LR was responsible for designing the study protocol, supervising the research, and reviewing the paper. YMG and HAK were responsible for supervising the research and helped in writing and reviewing the paper. ANS Doss performed the interpretation of the results and reviewing of the paper. EGA designated and performed the practical work, analysis, writing, reviewing, and editing of the paper. All authors read and approved the final version of the manuscript submitted for publication.

Corresponding author

Correspondence to Ebtehal Gamal Abdelhady.

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Ethics approval and consent to participate

All participants signed informed written consents with the declaration of data confidentiality. Ethical committee approval was obtained from Faculty of Medicine, Beni-Suef University. Approval No.: FMBSUREC/03012021/Sayed.

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Not applicable.

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The dataset supporting the conclusions of this article is included within the article.

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The authors have no relevant financial or non-financial interests to disclose.

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Gohary, Y.M., Abdelhady, E.G., Sayed, A.N. et al. Clinical study of Wnt inhibitory factor-1 expression and its association with disease severity in non-segmental vitiligo. Beni-Suef Univ J Basic Appl Sci 13, 89 (2024). https://doi.org/10.1186/s43088-024-00549-y

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  • DOI: https://doi.org/10.1186/s43088-024-00549-y

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