|Year : 2019 | Volume
| Issue : 3 | Page : 751-755
The role of osteopontin in dermatological diseases
Alaa H Marea1, Wafaa A Shehata1, Sally M El-Hefnawy2, Amany M Mohsen3
1 Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
3 Department of Dermatology, New Cairo Hospital, Cairo Health Sector, Cairo, Egypt
|Date of Submission||09-Jan-2018|
|Date of Acceptance||06-Mar-2018|
|Date of Web Publication||17-Oct-2019|
Amany M Mohsen
9 Elsawaf Street, Sector-10, Naser City, Cairo 11528
Source of Support: None, Conflict of Interest: None
The aim of this study was to study the role of osteopontin (OPN) in dermatological diseases through a meta-analysis study.
Previous literatures, reviews, and studies as well as medical websites (PubMed, Medscape and Science Direct), all material available in the internet from 2014 to 2017, and scientific journals databases were searched from the start date of each database.
The initial search presented 10 articles of which five met the inclusion criteria. Selection was done by supervisors for studying the role of OPN in dermatological diseases.
If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures.
Comparisons were made by a structured review with the results tabulated.
In total five potentially relevant publications were included; all were human studies. The studies show an elevated level of OPN in some dermatological diseases such as allergic contact dermatitis, alopecia areata, psoriasis, sarcoidosis, and systemic lupus erythematosus in comparison to the controls.
As OPN was elevated among allergic contact dermatitis, alopecia areata, psoriasis, sarcoidosis, and systemic lupus erythematosus patients, it may play a role in the pathogenesis of such diseases.
Keywords: alopecia areata, osteopontin, psoriasis, systemic lupus erythematosus
|How to cite this article:|
Marea AH, Shehata WA, El-Hefnawy SM, Mohsen AM. The role of osteopontin in dermatological diseases. Menoufia Med J 2019;32:751-5
| Introduction|| |
Osteopontin (OPN), a glycoprotein, was first identified in 1986 in osteoblasts. It is a multifunctional protein, highly expressed in the bone . The protein is composed of 314 amino acids, rich in aspartate, glutamate, and serine residues, and it contains functional domains for calcium binding .
It is encoded by the secreted phosphoprotein 1 (SPP1) gene, which maps to the long arm of chromosome 4 .
OPN exists in two distinct isoforms; secreted osteopontin (sOPN) and/or intracellular osteopontin (iOPN) protein. sOPN exerts its effect by binding to the cell surface receptors, expressed by target cells . sOPN is expressed in various tissues including the bone, mammary glands, kidneys, smooth muscle, brain, and the immune organs while the iOPN has been reported to be expressed in dendritic cells (DCs) and macrophages ,.
OPN regulates various biological activities including matrix remodeling and tissue calcification, monocytes/macrophages migration and chemotaxis, production of a variety of proinflammatory cytokines and chemokines, and inhibition of apoptosis activities .
T cells express OPN immediately after activation, suggesting that OPN is involved in immune reaction and host defense . By acting on macrophages, OPN upregulates interleukin-12 (IL-12) production and enhances T helper 1 (Th1) development. By acting on Th cells, OPN induces the production of IL-17 by triggering αvβ3 integrin and inhibits the secretion of IL-10 by triggering CD44 . By interacting with CD44 in Th cells, OPN induces hypomethylation of interferon-γ (IFN-γ) and IL-17a genes enhancing differentiation of Th1 and Th17 cells. In contrast, CD44 deficiency promotes hypermethylation of IFN-γ and IL-17a and hypomethylation of IL-4 gene, leading to Th2 cell differentiation .
There is evidence for a key role of OPN in Th1-mediated and Th17-mediated diseases  such as rheumatoid arthritis , psoriasis , and multiple sclerosis . It is demonstrated that OPN was involved in the pathogenesis of contact hypersensitivity dermatitis , systemic lupus erythematosus (SLE) , atherosclerosis, and cancer metastasis .
There is a possible role for OPN as an early cytokine capable of driving Th1 cells responses in psoriatic patients. In particular, OPN was reported to be capable of interacting with integrins and CD44 to enhance Th1 and to inhibit Th2 cytokine gene expression . sOPN produced by effector T cells attracts other immune cells to the inflammatory sites such as DCs, neutrophils, natural killer (NK) cells, NK-T cells, and macrophages . OPN has proangiogenic effects; it influences angiogenesis and proliferation of endothelial cells that allow robust influx of inflammatory effectors , which could be another possible contributing role of OPN in the pathogenesis of psoriasis that has been recognized as an angiogenesis-related disease .
It was also found that OPN secretion was important for the elicitation phase and the chronic phase of delayed-type allergic disease . The function of OPN was investigated during the sensitization phase of contact hypersensitivity. Serum OPN-guided Langerhans cells and myeloid DCs into skin-draining lymph nodes, induced the activation of DCs and polarized them toward a Th1-inducing phenotype .
The assumed role of OPN in alopecia areata (AA) could be based upon several facts: first, OPN exerts a Th1 cytokine function and is defined as a regulator of inflammatory cell accumulation and function at sites of inflammation and repair ,. Second, OPN is known to be expressed by inflammatory cells such as macrophages, DCs, NK cells, T cells, and B cells . These cells have been detected in the perifollicular infiltrates of AA and proved to be involved in its pathogenesis .
Systemic lupus erythematosus is originating in a deregulation of B and T lymphocytes, resulting in the production of autoantibodies . In mice, CD4−/CD8− T cells expressed high levels of OPN. Overexpression of OPN in the murine model of SLE induces B cell activation and immunoglobin IgG and IgM production, elevated autoantibodies (including antidouble-stranded DNA) levels and enhanced cytokine expression such as tumor necrosis factor-α, IFN-γ, and IL-1β .
Therefore, the aim of this work was to study OPN levels in these diseases in a trial to clarify its possible role in the pathogenesis of them.
| Materials and Methods|| |
We reviewed papers on the role of osteopontin in dermatological diseases from Medline databases (such as PubMed, Medscape, and Science Direct) and also from materials available in the Internet. We used osteopontin/alopecia areata/psoriasis/allergic contact dermatitis/sarcoidosis/systemic lupus erythematosus as the searching terms. In addition, we examined references from the specialist databases EMF-Portal (http://www.emf-portal.de). The search was performed in the electronic databases from 2014 to 2017.
All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:
Inclusion criteria of the published studies:
- Published in English language
- Published in peer-reviewed journals
- Focused on OPN in dermatological diseases
- Discussed the relation between pigmentary disorders and vitamin D
- If a study had several publications on certain aspects we used the latest publication giving the most relevant data.
If the studies did not fulfill the above criteria, they were excluded such as, report without peer-review, not within the national research program, letters/comments/editorials/news, and studies not focused on OPN.
The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid.
US Preventive Services Task Force:
Level I: evidence obtained from at least one properly designed randomized controlled trial
Level II-1: evidence obtained from well-designed controlled trials without randomization
Level II-2: evidence obtained from a well-designed cohort or case–control analytic studies, preferably from more than one center or research group
Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that the confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.
A structured systematic review was performed.
| Results|| |
Study selection and characteristics
In total, 10 potentially relevant publications were identified: five articles were excluded as they did not meet our inclusion criteria. A total of five studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. All these studies were human, case, and control studies, and examined the level of OPN and its role in some dermatological diseases such as allergic contact dermatitis, AA, psoriasis, sarcoidosis, and systemic lupus erythematosus. They were reviewed from Medline databases (PubMed, Medscape, and Science Direct). The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM. A structured systematic review was performed.
All of the included studies showed higher levels of OPN [Table 1].
|Table 1: Summary of studies showing the elevated level of osteopontin in some dermatological diseases|
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A randomized, controlled trial by Rrduta et al. , studied 24 patients with numerous allergic contact dermatitis (ACD) lesions and 22 age-matched and sex-matched healthy patients as a control group. Serum OPN levels were measured in the ACD patients twice: in the acute stage and during disease remission by enzyme-linked immunosorbent assay. Results showed that the serum OPN concentrations were significantly increased in patients with disseminated ACD examined in the acute stage as compared with healthy patients and ACD patients during remission. In the ACD patients with extensive skin lesions, OPN serum levels were significantly higher than in those with mild disease.
Additionally, Ganzetti et al.  had a retrospective case–control study on 40 patients affected by AA (23 men and 17 women; mean age 40.25 ± 6.35; range: 20–55), both before (T0) and after 12 months (T12) of treatment with 2,3-diphenilcyclopropenone (DPCP), and 20 controls obtained from healthy patients matched for sex and age. Results showed that the plasma OPN value in patients with AA was significantly higher than in healthy controls; however, the plasma levels of OPN did not correlate with severity and duration of AA. There was no statistically significant decrease of mean plasma levels of OPN after DPCP treatment, although it was significantly higher than in healthy patients.
Abdel-Mawla et al.  had a case–control study on 18 (eight men and 10 women) patients of chronic plaque psoriasis; their ages ranged between 12 and 64 years, and a control group of 18 apparently healthy volunteers matched for sex and age. Two skin biopsies were taken from psoriatic patients. The first was taken from the lesional skin and the other from a counter apparently healthy site. Results showed statistically significant differences in the expression of OPN, between lesional and nonlesional skin as well as between nonlesional skin and control group. In addition, there was a significant difference in the expression of OPN between control and lesional groups.
Lavi et al.  in a case–control study, studied 113 patients with sarcoidosis and 79 healthy controls. Blood samples were analyzed for single nucleotide polymorphism (SNPs) of the OPN gene and for plasma OPN levels. The association between clinical features of disease and OPN levels as well as SNP frequencies was determined. Results showed that plasma OPN levels were higher in sarcoidosis patients than in healthy patients. No differences were observed between sarcoidosis patients and controls in the frequency of any of the SNPs evaluated. Also there is no correlation between SNPs distribution and plasma OPN levels.
Another case–control study was done by Wirestam et al. , on 240 adult SLE cases (208 women, 32 men; mean age 49 years; range: 18–88 years) and 240 population-based controls matched for age and sex. The sera were immunoassayed for OPN.
Results showed that serum OPN levels were on average raised fourfold in SLE cases compared with the controls. There were no statistically significant differences between men and women among the patients, nor among the controls.
| Discussion|| |
OPN is a multifunctional protein that plays an important role in the inflammatory processes inhibiting Th2 response and promoting Th1 cytokine function, with a crucial role in leukocyte migration . It is secreted in autoimmune diseases such as lupus erythematosus, and influences inflammation of immediate and delayed-type allergies and granuloma formation. It is overexpressed in psoriasis .
Seier et al.  hypothesized that OPN, an immune mediator that has been shown to worsen the effects of autoimmune disease, played a role in eliciting and facilitating chronic allergic contact dermatitis. They found that both skin cells and immune cells sOPN in allergic contact dermatitis lesions.
Ganzetti et al.  study showed that OPN plasma levels in patients with AA were higher than in healthy controls, and it could be hypothesized that OPN has a role in the pathogenesis of AA, amplifying the inflammatory cascade. Also they noted that the OPN plasma level increases in patients with AA recurrence after DPCP discontinuation. Thus, they hypothesize that increased serum levels of OPN could be a primitive facilitating factor in AA pathogenesis.
As regards studies in psoriasis, OPN appears to have a role in disease development through inhibiting keratinocyte apoptosis, thereby supporting enhanced epidermal proliferation; sOPN promotes vessel formation subsequently supporting the influx of inflammatory cells. OPN has a proangiogenic effect on microvascular endothelial cells and has been involved in the onset of angiogenesis through a mechanism mediated by IL-1 .
A statistically significant difference was found between psoriatic patients and controls regarding OPN expression in the epidermal skin layers between lesional and nonlesional skin groups, nonlesional and control groups, and finally, lesional skin and control groups. These results possibly indicate that in some psoriatic patients, nonlesional skin might be predisposed to develop the disease, as it can occur in the so-called Koebner phenomenon may be due to elevated OPN expression .
Plasma OPN may be a suitable marker for the presence of sarcoidosis . They considered whether plasma OPN could be of use as a biomarker to diagnose sarcoidosis or as a marker of disease activity and of response to treatment. As regards diagnosis, receiver operator curves for OPN show a diagnostic value (area under the curve) of 0.798, which is similar or slightly better than the existing markers, which are being used routinely. For example, the angiotensin-converting enzyme, which is known to be nonspecific and increased in neoplastic and chronic infectious conditions, was found to have an area under the curve of 0.779 .
Increased levels of OPN have been reported also in the sera and plasma of SLE patients and their use has been suggested in monitoring SLE severity . In line with these observations, a prospective study suggested that high plasma levels of OPN may be predictors of poor outcome and are associated with the presence of auto Antibodies (Abs) anti-ds-DNA and elevated IFN-α level in the serum . Moreover, high OPN levels in the serum and glomeruli are associated with renal damage, possibly mediated by the ability of OPN to support the secretion of Th1 and Th17 proinflammatory cytokines and inflammatory cell migration and activation .
| Conclusion|| |
This review indicates an association between OPN and dermatological diseases. It has an important function in immune-mediated skin inflammation, which may open the perspective to use anti-OPN antibody preparations for the treatment of such diseases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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