Comprehensive bioinformatics analysis and experimental validation reveal the role of circadian rhythm–related genes in the crosstalk between osteoporosis and atherosclerosis

Mar 28, 2026Mammalian genome : official journal of the International Mammalian Genome Society

Circadian rhythm genes linked to the connection between bone loss and artery disease

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Abstract

A total of 69 common genes were identified that may link osteoporosis and atherosclerosis through circadian rhythm-related mechanisms.

Circadian rhythm activity is significantly enriched in bone marrow stromal cells in osteoporosis and vascular smooth muscle cells in atherosclerosis.
In human bone marrow samples, nine cell lineages with 17 subpopulations were identified, while six cell lineages with 18 subpopulations were found in carotid artery samples.
was notably upregulated in both naturally aged and adenine-induced mice, with changes in other gene expressions related to vascular calcification.
The study highlights the potential role of circadian rhythm-related regulation in the coexistence of osteoporosis and atherosclerosis.

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Osteoporosis (OP) and atherosclerosis (AS) are increasingly prevalent in aging populations and frequently coexist, sharing pathological features such as abnormal vascular calcification. However, the common marker genes underlying the crosstalk between OP and AS remain poorly understood. This study aimed to identify shared marker genes and cellular mechanisms contributing to the coexistence of OP and AS. Single-cell RNA sequencing (scRNA-seq) dataset and mRNA expression profiles related to OP and AS were obtained from the Gene Expression Omnibus (GEO) database. Bioinformatics analyses were performed using the R packages Seurat, AUCell, and hdWGCNA to identify circadian rhythm-related genes (CRGs) and associated cell populations. Naturally aged mice and a 0.25% adenine (AD)-induced mouse model were established. Micro-computed tomography (µCT), immunohistochemistry (IHC), immunofluorescence, Von Kossa staining, and RT-qPCR were conducted to experimentally validate the identified common genes. In human bone marrow samples, nine cell lineages comprising 17 subpopulations were identified, while six cell lineages comprising 18 subpopulations were identified in carotid artery samples. Circadian rhythm activity was significantly enriched in bone marrow stromal cells (BMSCs) in OP and vascular smooth muscle cells (VSMCs) in AS. By integrating scRNA-seq and bulk RNA-seq analyses, 69 common genes were identified, of which 15 hub genes were further selected through protein-protein interaction (PPI) network analysis. Experimental validation demonstrated that was markedly upregulated in both naturally aged and AD-induced mice, accompanied by increased PLIN1 expression, reduced osteocalcin (OCN) expression, and enhanced vascular calcification. This study reveals that circadian rhythm-related regulation of BMSCs in OP and VSMCs in AS plays a critical role in their coexistence. Furthermore, we identify shared marker genes, particularly AEBP1, which may serve as potential biomarkers and therapeutic targets for the concurrent development of OP and AS.

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Common Genes Identified

Common circadian rhythm-related genes between OP and AS.

Upregulated Expression

expression validated in aged and adenine-induced vascular calcification mouse models.

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Comprehensive bioinformatics analysis and experimental validation reveal the role of circadian rhythm–related genes in the crosstalk between osteoporosis and atherosclerosis

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