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Meta-analysis of GLP1R, GIPR, ADCY3, and CREB1 expression in osteoarthritis identifies CREB1 as a potential biomarker
1School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
Background:
Osteoarthritis (OA) is a progressive joint disease with no disease-modifying therapies. Incretin-related signaling pathways, including GLP1R, GIPR, ADCY3, and CREB1, may influence cartilage homeostasis and inflammation, but their transcriptional profiles across cohorts remain unclear. To evaluate the expression, diagnostic potential, and functional context of GLP1R, GIPR, ADCY3, and CREB1 in OA cartilage through an integrative meta-analysis of public transcriptomic datasets.
Methods:
We systematically searched the GEO database, identifying 147 records. After screening and applying inclusion criteria, four datasets were included (GSE114007, GSE117999, GSE169077, GSE220243; total N = 83). Expression data were normalized within each dataset, converted to per-gene z-scores, and analyzed using random-effects meta-analysis. Machine learning classifiers (logistic regression, random forest, XGBoost) were trained with leave-one-dataset-out validation. Functional enrichment was performed using g:Profiler. Protocol registration: PROSPERO CRD420251177348.
Results:
CREB1 (pooled mean difference +0.459, p = 0.036) and GLP1R (+0.518, p = 0.016) were significantly upregulated in OA cartilage, ADCY3 was downregulated (-0.552, p = 0.010), while GIPR showed no significant change. Heterogeneity was low (I2 = 0 % for CREB1, GLP1R, ADCY3). In classification, logistic regression achieved the highest pooled discrimination (AUC = 0.684), but performance varied across cohorts, indicating modest diagnostic power under external validation. Enrichment analysis highlighted cAMP-mediated signaling and Gαs-coupled GPCR pathways converging on CREB1.
Conclusion:
A multi-cohort transcriptomic analysis suggests the involvement of a GLP1R-ADCY3-cAMP-CREB1 axis in OA cartilage, with reproducible upregulation of CREB1 and GLP1R. Although sample-level classification was modest, pathway-level signals and experimental evidence support CREB1 as a biomarker candidate and therapeutic target. These findings provide a rationale for prospective validation studies and translational exploration of incretin-pathway modulation in OA.
Insights
This study found that CREB1 and GLP1R are upregulated in osteoarthritis (OA) cartilage, while ADCY3 is downregulated. These findings suggest a potential therapeutic pathway for OA.
Area of Science:
- Genomics
- Molecular Biology
- Biochemistry
Background:
- Osteoarthritis (OA) is a degenerative joint disease lacking disease-modifying treatments.
- Incretin signaling pathways (GLP1R, GIPR, ADCY3, CREB1) may impact cartilage health and inflammation.
- Transcriptional profiles of these pathways in OA cartilage are not well understood.
Purpose of the Study:
- To investigate the expression of GLP1R, GIPR, ADCY3, and CREB1 in OA cartilage.
- To assess the diagnostic potential of these genes in OA.
- To explore the functional context of these genes in OA pathogenesis through meta-analysis.
Main Methods:
- Systematic search of the GEO database for relevant transcriptomic datasets.
- Inclusion of four datasets (GSE114007, GSE117999, GSE169077, GSE220243) comprising 83 samples.
- Meta-analysis of normalized gene expression data using random-effects models and machine learning classifiers.
- Functional enrichment analysis using g:Profiler.
Main Results:
- CREB1 and GLP1R were significantly upregulated in OA cartilage (p < 0.05).
- ADCY3 was significantly downregulated (p = 0.010).
- GIPR showed no significant expression change; logistic regression achieved modest diagnostic power (AUC = 0.684).
Conclusions:
- A GLP1R-ADCY3-cAMP-CREB1 axis is implicated in OA cartilage.
- CREB1 and GLP1R upregulation is reproducible across cohorts.
- CREB1 shows potential as a biomarker and therapeutic target for OA, warranting further validation.
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