Vitamin D mediates crosstalk between COVID-19 and osteoporosis

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

Several types of COVID-19 vaccines have been developed, many of which have received approval from global regulatory bodies. However, genomic mutations have led to the emergence of new SARS-CoV-2 variants, which have 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 numerous vaccines capable of preventing severe disease, there remains a lack of specific and effective treatments against COVID-19. Thus, healthcare providers have primarily provided symptomatic treatment to these patients.

Low plasma 25(OH)-vitamin D (VitD) levels are considered an independent risk factor for COVID-19 incidence. Hypovitaminosis D, defined as a VitD deficiency, has also been detected in severely infected COVID-19 patients. To a certain extent, the presence of both COVID-19 and hypovitaminosis D has been 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 can help prevent cardiovascular complications, multiple organ failure, and other complications associated with the cytokine storm in COVID-19 patients.

Recently, osteoporosis patients were found to be more susceptible to SARS-COV-2 infection. Some COVID-19 patients who have recovered from the illness reported worsened osteoporosis conditions. As a result, these patients were commonly treated with Vit D supplements.

Osteoporosis is a condition that occurs due to Vit D deficiency. To date, limited studies have described how Vit D deficiency is linked with osteoporosis and COVID-19 manifestation.

A recent study under review in the journal Scientific Reports and currently available on the Research Square* preprint server utilized bioinformatics, network pharmacology, and molecular docking approaches to identify and characterize the targets of Vit D on 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, thus indicating that these two conditions might 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 intermediate crosstalk between COVID-19 and osteoporosis.

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

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

Study findings

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

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

Vit D also appears to induce osteoimmune mechanisms and control the structural integrity of bones. The mechanism associated with the binding between Vit D and both EGFR and MAPK8 proteins was also validated through molecular docking simulations.

The present study indicates that Vit D might inhibit the immune response of SARS-CoV-2 infected patients to inhibit the pathological processes involved with the incidence of fibrosis and pulmonary inflammation.

In SARS-CoV-2 infected patients, pulmonary fibrosis occurs through the EGFR-mediated ERBB signaling pathway that is responsible for the production of 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.

Conclusions

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

Vit D bound tightly and interacted with MAPK8 and EGFR. Vit D targets associated with the ErbB and MAPK signaling pathways have an important role in the regulation of bone structural integrity, immune responses, and lung fibrosis.

Taken together, the current study provided novel mechanistic insights into the functional roles of Vit D in both COVID-19 and osteoporosis. Thus, Vit D levels can be used to indicate a potentially poor prognosis of COVID-19 and osteoporosis. Supplementation of Vit D 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 regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.