Identification and validation of the shared signature gene MMP9 and ANGPTL4 and its regulatory mechanisms in Type 2 Diabetes combined with Osteoarthritis

Abstract

Objective Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are prevalent diseases significantly impacting patients' quality of life. Increasing evidence suggests a correlation between T2D and OA, yet their molecular mechanisms remain elusive. Our study aims to investigate shared biomarkers and potential molecular mechanisms underlying these diseases. Methods Gene expression profiles for T2D and OA were sourced from the Gene Expression Omnibus (GEO) database.We employed bioinformatics to identify differentially expressed genes (DEGs) common to T2D and OA. Subsequently, functional annotation, and protein-protein interaction (PPI) analyses were conducted on these DEGs, leading to the preliminary identification of hub genes. Further validation of these hub genes' mRNA expression was achieved using external T2D and OA datasets, culminating in identifying pivotal genes. Western blotting and qRT-PCR techniques validated the expression of these key genes in clinical case samples. The accuracy of the key genes as predictive biomarkers for T2D and OA were assessed using the receiver operating characteristic curve (ROC). We developed a network of interactions between transcription factors (TFs) and microRNAs (miRNAs) .Finally, we identified the most promising therapeutic agents through molecular docking. Results We identified 209 shared DEGs between T2D and OA. Functional analysis revealed that these DEGs were predominantly associated with ossification, regulation of leukocyte migration, extracellular matrix (ECM) structural constituent, PI3K/AKT and Wnt signaling pathways. PPI analysis and external datasets validation highlighted MMP9 and ANGPTL4 as pivotal genes in T2D and OA. ANGPTL4 regulates glucose metabolism, osteoclast-mediated bone resorption, cartilage degradation, whereas MMP9 plays a role in ECM degradation and inflammatory responses. Both qRT-PCR and Western blot analyses confirmed high expression levels of pivotal genes in T2D, OA, T2D combined with OA cases.Analysis of TFs-miRNAs interactions identified 7 TFs and one miRNA that collectively regulate pivotal genes. ROC analysis underscored the strong diagnostic potential of MMP9 and ANGPTL4. Raloxifene, Ezetimibe, and S-3304 were also identified as promising therapeutic agents for patients with T2D and OA. Conclusion This study uncovers shared signaling pathways, biomarkers, potential therapeutics, and diagnostic models for T2D and OA. These findings offer novel perspectives on the pathogenesis, diagnosis, and treatment of T2D when co-occurring with OA.