Asthma is a heterogenic, chronic inflammatory disease characterized by reversible obstruction and airway hypersensitivity.1 The identification of similar biological biomarkers which play a role in inflammation in asthma patients is important with regard to both diagnosis and the developments it will provide for treatment. The identification of special non-invasive biomarkers that will enable monitoring and follow up is of greater importance, especially in childhood asthma cases. Spirometric measurements used frequently for this purpose require effective cooperation and therefore cannot be sufficiently evaluated in children. Similarly, current methods such as bronchoalveolar lavage cannot be routinely used because they are invasive.2–5 Hence, there is a need for non-invasive methods that may be used for the follow up of these diseases.

Initially, osteoprotegerin (OPG) is a polypeptide synthesized with 401 amino acids. A mature protein composed of 380 amino acids is formed after removing the 21 amino acid propeptide section. It is secreted extracellularly as a homodimeric, soluble glycoprotein with 60kDa monomeric and 120kDa disulfite bond. OPG is a member of the tumor necrosis factor receptors (TNFR) super family but does not contain transmembrane and cytoplasmic sections like the other receptors of the TNFR super family.6,7 OPG is synthesized by many different tissues, including hematopoietic and immune cells such as osteoblasts, bone marrow, kidney, spleen, brain, lung and cardiovascular system (heart, arteries and veins).8,9 The primary function of OPG is known as osteoclast differentiation and activation inhibition, however the role played by OPG synthesized in other tissues is not known for sure. OPG synthesis in large arteries’ media layers and different vascular cell types such as coronary artery smooth muscles and endothelium cells indicate its function at the vascular bed.10

The role played by OPG, a glycoprotein mediator in the lung and macrophages, in childhood asthma and the relationship between its level and disease severity is not known. The number of studies with invasive bronchoscopy techniques in children is limited, hence studies have focused more on identifying various markers for determining airway inflammation. In this study it was planned to evaluate the relationship between OPG levels and airway inflammation in childhood asthma and the assessment of its usability as a biomarker.

The average age of asthma patients was 10.61±3.04 years. 51.2% were female and 64.1% were atopic. Dust mite sensitivity was present in all patients. Statistically significant differences were not observed between the average ages, gender distributions, birth weight, birth week, birth type, smoking during pregnancy, household smoking, atopic dermatitis, having a pet, household humidity and heating distributions of healthy cases and cases with asthma (p>0.05). A statistically significant difference was observed in the atopic asthma group regarding atopy in the family and allergic rhinitis (p<0.001) (Table 1). A statistically significant difference could not be observed between the serum OPG levels of the groups (p>0.05) (Table 2). No statistically significant difference was observed between the PEF, FEV1/FVC measurements and IgE, eosinophil count and OPG levels of asthma patients upon evaluating the spirometric measurements and correlation analyses of asthma patients (p>0.05). A negative and statistically significant correlation was observed between the FEV1 and FVC values and OPG levels (p=0.015, p=0.003) (Table 3).

In this study examining the relationship between serum OPG levels and respiratory functions and airway inflammation in children with asthma and assessing its use as a biomarker, the OPG levels of asthma cases measured during the stable period were determined to be similar with those of the healthy group.

OPG was originally discovered as an inhibitor of bone resorption, and various cytokines and hormones regulate its expression and production.11 Besides the significant role it plays with regard to the regulation of bone metabolism, osteoprotegerin has important anti-inflammatory and anti-apoptotic effects.12 It neutralizes the effect of receptor activator of nuclear factor-κ B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) thus inhibiting the activation of specific pro-inflammatory and pro-apoptotic signaling pathways.13 Studies put forth that dendritic cells have abnormal activation in asthma patients.14–16 However, the impact of osteoprotegerin on inflammation in asthma could not be explained clearly since there is not sufficient knowledge of its impacts on RANK/RANKL signal inhibition and the life and function of the dendritic cells in the lungs. Yang et al.17 carried out related studies on rat models with asthma and showed that OPG as a RANK/RANKL signal inhibitor may reduce the inflammatory reaction in asthma by preventing the life and function of dendritic cells.

Anand et al.18 carried out a study on 510 patients with type 2 diabetes for examining the relationship between OPG, inflammation biomarkers of hs-CRP, IL-6 and coronary artery calcification and cardiovascular disease as a result of which a strong relationship was put forth between the plasma OPG levels and increased coronary artery calcification. It is also reported that OPG is involved in lipopolysaccharide-induced acute inflammation in animal models.19 13 Coronary artery disease, rheumatoid arthritis, and some other diseases cause an increase in serum OPG levels and thus it has been used as a biomarker.20,21

As far as we know, there is no study in the literature which examines the relationship between OPG levels and airway inflammation in children with asthma. Masako et al.22 carried out a study on patients with chronic obstructive pulmonary disease (COPD) and showed that phlegm OPG levels were observed to be higher in patients with COPD in comparison to healthy controls and those of smokers were observed to be higher in comparison to asthma patients. OPG levels of COPD patients were similar compared with the control group. They believe the reason for these results is because OPG is the biomarker of a local inflammation instead of a systemic inflammation. They also reported that phlegm OPG concentrations in COPD patients are negatively correlated with FEV1, which may be related with the course and severity of the disease. In conclusion, the authors put forth that OPG levels in the phlegm of patients with COPD are correlated with the lung function changes indicating parenchymal damage but that there is a need for more comprehensive studies in order for OPG to be used as a bio-biomarker for emphysema. In accordance with the related literature, in our study, the serum OPG levels of patients with asthma were determined to be at similar levels with the serum OPG levels of healthy cases. Similarly, a negative and statistically significant correlation was observed between the FEV1 and FVC values and osteoprotegerin levels.

Some authors reported an increase in serum IgE levels whilst a decrease in FEV1 levels.23,24 Kumar et al.23 stated a statistically significant weak negative correlation between serum IgE and FEV1 levels (p=0.04) (r=−0,23). Di Lorenzo et al.24 suggested a positive correlation between both serum IgE and eosinophil numbers, and bronchial hyperactivity in patients with Parietaria pollen hypersensitivity. They also stated that beside eosinophils, allergen types and IgE levels could play a role in the development of bronchial hypersensitivity and asthma progression in allergic rhinitis patients. In the same research mentioned above, Kumar et al.23 showed that, while there is no significant correlation between serum eosinophil numbers and respiratory function tests (r=-0.95), there is a weak negative correlation between sputum eosinophil and FEV1, FVC levels (p=0.011) (p=0.015). Our study shows no statistically substantial relation between FEV1, FVC, IgE and serum eosinophil levels. The reason for the obtained result might be the lack of severe asthma patients.

We are of the opinion that the limitations of our study are the low number of patients, the fact that the patients with asthma have been evaluated during the stable period and that there are no severe asthma cases included in the study.

Our study is the first study on the relationship between osteoprotegerin levels and airway inflammation in children with asthma. We believe that there is a requirement for wider scale studies in which clinical symptoms and more parameters are evaluated preferably with phlegm and/or BAL evaluations for defining the role played by osteoprotegerin in children with asthma and for determining its usability as a marker.

Not applicable.

Nacaroglu, Hikmet Tekin: literature search, study design, data collection, manuscript preparation/editing, final manuscript approval

Büke Övgü: literature search, study design, data collection, manuscript preparation/editing, final manuscript approval

Bostan Gayret Ozlem: literature search, manuscript preparation/editing, data analysis

Erol Meltem: literature search, data collection, data analysis, data interpretation

Zengi Oguzhan: literature search, data collection, data analysis, data interpretation

The authors have no financial relationships relevant to this article to disclose.

No external funding was secured for this study.

The authors have no conflicts of interest to disclose.