Bioinformatics analysis combined with experiments to unveil common hub genes, pathways, and transcription factor regulatory networks in ulcerative colitis and osteoporosis

Background

Osteoporosis (OP) is a common comorbidity in ulcerative colitis (UC) patients. However, the specific mechanism by which UC induces bone loss remains unclear.

Methods

Transcriptome data from the GSE87466 and GSE35958 datasets were analyzed to identify common differentially expressed genes (co-DEGs), construct protein-protein interaction network, and perform functional enrichment analysis. The R packages PROGENy, NetAct, and sRACIPE were used to infer the activity of the signaling pathways, construct transcription factor regulatory networks, and identify disease-promoting genes. A dextran sulfate sodium (DSS)-induced UC mouse model was established to validate the biological processes enriched among co-DEGs.

Results

A total of 66 upregulated co-DEGs were identified, with ICAM1, ITGA5, THY1, ITGB2, TGFB1, MMP2, COL6A2, FLNA, CD5, and IL16 identified as hub genes. These upregulated co-DEGs were significantly enriched in processes, such as response to cytokine, leukocyte transendothelial migration, regulation of myeloid leukocyte mediated immunity, and osteoclast differentiation. Seven signaling pathways, NF-κB, TNF-α, MAPK, EGFR, TGF-β, hypoxia, and TRAIL, were consistently activated in both UC and OP. A total of 12 genes were identified as disease-suppressing and 22 as disease-promoting in UC, while 7 genes were found to be disease-suppressing and 5 disease-promoting in OP. Among these, RELA, NFKB1, and FOS were found to be common disease-promoting genes in both UC and OP. DSS administration in mice not only induced colitis, but also resulted in significant bone loss, likely driven by TNF-α–mediated enhancement of bone resorptive activity.

Conclusions

UC-related colonic inflammation triggers cytokine release and promotes immune cell activation and trafficking into the bone marrow microenvironment. Key inflammatory mediators, particularly TNF-α, act synergistically with receptor activator of nuclear factor kappa-Β ligand (RANKL) to enhance the differentiation of osteoclast precursors into mature osteoclasts. This inflammatory milieu accelerates bone resorption and ultimately leads to bone loss and structural degradation. These findings suggest three potential dual-targeted therapeutic strategies for UC and OP: inhibiting TNF-α, targeting leukocyte migration-related hub genes (ICAM1, ITGA5, ITGB2, and TGFB1), and inhibiting common disease-promoting genes (RELA, NFKB1, and FOS).