Vitamin D mediates crosstalk between COVID-19 and osteoporosis

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The global outbreak of the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has led to the coronavirus disease 2019 (COVID-19) pandemic, which has claimed more than 6.4 million lives worldwide. world to date.

Several types of COVID-19 vaccines have been developed, many of which have received approval from global regulators. However, genomic mutations led to the emergence of new SARS-CoV-2 variants, which reduced the effectiveness of these vaccines.

Study: COVID-19 and osteoporosis: shared mechanisms and crosstalk via vitamin D. Image Credit: Jarun Ontakrai/Shutterstock.com

Background

Despite the development of many vaccines capable of preventing serious diseases, there remains a lack of specific and effective treatments against COVID-19. Thus, health care providers mainly provided symptomatic treatment for these patients.

Low plasma 25(OH)-vitamin D (VitD) levels are considered an independent risk factor for the incidence of COVID-19. Hypovitaminosis D, defined as VitD deficiency, has also been detected in patients severely infected with COVID-19. To some extent, the presence of COVID-19 and hypovitaminosis D was a predictor of hospitalization and mortality.

A reduction in inflammatory markers has been observed in COVID-19 patients treated with Vit D. Additionally, the immunomodulatory activities of VitD may help prevent cardiovascular complications, multiple organ failures, and other complications associated with storm of cytokines in COVID-19 patients.

Recently, patients with osteoporosis have been found to be more susceptible to SARS-COV-2 infection. Some COVID-19 patients who have recovered from the disease have reported worsening osteoporosis. As a result, these patients were usually treated with vitamin D supplements.

Osteoporosis is a condition caused by vitamin D deficiency. To date, limited studies have described how vitamin D deficiency is related to osteoporosis and the outbreak of COVID-19.

A recent study being reviewed in the journal Scientific Reports and currently available on the Research Square* The preprint server used bioinformatics, network pharmacology, and molecular docking approaches to identify and characterize vitamin D targets in COVID-19 and osteoporosis.

About the study

A total of 2,660 COVID-19 targets, 5,093 osteoporosis targets and 243 vitamin D targets were identified using bioinformatics and network pharmacology approaches. A Venn diagram predicted that 855 targets were shared between COVID-19 and osteoporosis, indicating that these two conditions may have a shared mechanism of pathogenesis.

A total of 42 targets were found to be shared between COVID-19, osteoporosis and VitD. This finding indicates that VitD may interfere with crosstalk between COVID-19 and osteoporosis.

A drug-target-disease (DTD) network of Vit D-COVID-19-Osteoporosis was then constructed based on protein-protein interaction (PPI) data obtained by network pharmacology. This network identified eight of 42 targets as possible prime targets for vitamin D in the regulation of COVID-19 and osteoporosis.

These eight primary targets were subjected to gene ontology (GO) enrichment analysis, KEGG pathway enrichment analysis, Wiki Pathways, and Reactome pathway enrichment analysis. Furthermore, the biological process (BP) regulatory role of VitD, through cellular responses to reactive oxygen species (ROS) and estrogen stimulation, was elucidated by GO analysis.

Study results

Screening of signaling pathway databases revealed that ErbB and mitogen-activated protein kinase (MAPK) signaling pathways were co-expressed in KEGG and Wiki Pathways. These databases further showed the activation of the activator protein-1 (AP-1) family of transcription factors in the KEGG endocrine resistance pathway in the Rectome immune system. These shared pathways also exhibited common targets, such as endothelial growth factor receptor (EGFR), ErbB2, and MAPK8.

Both EGFR and MAPK8 targets have been shown to be involved in G-protein-coupled receptor (GPCR) signaling, cytokine signaling in the immune system, and vesicle-mediated transport. These results indicate that Vit D exerts its regulatory functions through activation of MAPK, while ErbB signaling pathways ameliorate pulmonary fibrosis and control cytokine storm in COVID-19 patients.

Vitamin D also seems to induce osteo-immune mechanisms and control the structural integrity of bones. The mechanism associated with the binding between Vit D and the proteins EGFR and MAPK8 was also validated by molecular docking simulations.

The present study indicates that vitamin D may inhibit the immune response of patients infected with SARS-CoV-2 to inhibit disease processes involved in the incidence of lung fibrosis and inflammation.

In patients infected with SARS-CoV-2, pulmonary fibrosis occurs through the EGFR-mediated ERBB signaling pathway which is responsible for producing more pro-fibrotic than anti-fibrotic effects. Conversely, VitD binds to the MAPK signaling pathway to facilitate osteoimmunity and contribute to muscle growth and regeneration.

conclusion

Major targets associated with the Vit D-COVID-19-osteoporosis network include estrogen receptor 1 (ESR1), EGFR, microtubule-associated protein tau (MAPT), MAPK8, ERBB2, AR, double minute mouse 2 ( MDM2) and zest homolog enhancer 2 (EZH2).

Vitamin D binds tightly and interacts with MAPK8 and EGFR. Vit D targets associated with ErbB and MAPK signaling pathways play important roles in the regulation of bone structural integrity, immune responses, and pulmonary fibrosis.

Overall, the present study has provided new mechanistic insights into the functional roles of vitamin D in COVID-19 and osteoporosis. Thus, Vit D levels can be used to indicate a potentially poor prognosis of COVID-19 and osteoporosis. Vitamin D supplementation could be beneficial for the prevention and treatment of these diseases.

*Important Notice

Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

Journal reference:

  • Liu, F., Song, C., Cai, W., et al. (2022) COVID-19 and osteoporosis: shared mechanisms and crosstalk via vitamin D. Research Square. doi:10.21203/rs.3.rs-1887098/v1.
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