Shared mechanisms and crosstalk of COVID-19 and osteoporosis via vitamin D

Abstract

Recently accumulated evidence implicates a close association of vitamin D (VitD) insufficiency to the incidence and clinical manifestations of the COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). Populations with insufficient VitD including patients with osteoporosis are more susceptible to SARS-COV-2 infection and patients with COVID-19 worsened or developed osteoporosis. It is currently unknown, however, whether osteoporosis and COVID-19 are linked by VitD insufficiency. In this study, 42 common targets for VitD on both COVID-19 and osteoporosis were identified among a total of 243 VitD targets. Further bioinformatic analysis revealed 8 core targets (EGFR, AR, ESR1, MAPK8, MDM2, EZH2, ERBB2 and MAPT) in the VitD-COVID-19-osteoporosis network. These targets are involved in the ErbB and MAPK signaling pathways critical for lung fibrosis, bone structural integrity, and cytokines through a crosstalk between COVID-19 and osteoporosis via the VitD-mediated conventional immune and osteoimmune mechanisms. Molecular docking confirmed that VitD binds tightly to the predicted targets. These findings support that VitD may target common signaling pathways in the integrated network of lung fibrosis and bone structural integrity as well as the immune systems. Therefore, VitD may serve as a preventive and therapeutic agent for both COVID-19 and osteoporosis.

Figure 1

Venny diagram of the association of VitD targets with osteoporosis and COVID-19 targets. A total of 243 VitD targets, 2660 COVID-19 targets, and 5093 osteoporosis targets were identified. There exist 855 common targets between COVID-19 and osteoporosis, 59 common targets between VitD and COVID-19, 124 common targets between VitD and osteoporosis, and 42 common targets among VitD, COVID-19 and osteoporosis.

Figure 2

Protein–protein-interaction (PPI) map of "Drug-Targets-Disease”. Network nodes represent proteins, i.e. each node represents all proteins produced by a single protein-coding locus. The edges represent protein–protein associations, where associations are meant to be specific and meaningful, i.e. proteins together contribute to a common function. Network Statistics: Nodes: 42, Edges: 117, Average Node Degree: 5.57, Local Clustering Coefficient: 0.53, Expected Edges: 56, PPI Enrichment p-Value: 7.72e-13.

Figure 3

Drug-Targets-Disease Interaction Network. Graphs were constructed to link VitD to osteoporosis and COVID-19 targets. VitD can act on osteoporosis and COVID-19 through the 42 targets shown.

Figure 4

Core targets. This figure shows the core target map obtained based on 42 common targets constructed by PPI, based on topological heterogeneity analysis and setting twofold average node degree. Among them, EGFR and MAPK targets have the most interactions with other targets among the core targets, and thus they play a crucial role in the treatment of diseases.

Figure 5

Advanced histogram of GO biological process analysis. In this study, 724 GO terms were identified, including 632 biological processes (BP), 26 cellular components (CC) and 66 molecular functions (MF). The top 10 most important terms for BP, CC and MF are clearly shown by the bar chart.

Figure 6

Advanced bubble diagram of KEGG pathway enrichment analysis. By KEGG pathway enrichment analysis, 34 pathways were obtained, and the top 10 important pathways were shown by bubbles through screening.

Figure 7

ERBB signaling pathway. The mechanisms of action of the ERBB signaling pathway that has been identified so far.

Figure 8

MAPK signaling pathway. The mechanism of action of the MAPK signaling pathway that has been identified so far.

Figure 9

Rectome analysis. The diagrams show the human systems and locations of cellular responses involved in the core targets' actions, etc. The eight core targets focus on the immune system, the innate immune system, cytokine signaling in the immune system, signaling in the GPCR, vesicle-mediated transport, and other signaling pathways. Among these, the mechanisms involved in the immune system make it a priority for us to understand and study in depth.

Figure 10

Docking pattern diagram of VitD with EGFR (A) and MAPK8 (B) The molecular docking pattern plots for VitD with EGFR (A) and MAPK8 (B), respectively.