Effect of the Abnormal Expression of BMP-4 in the Blood of Diabetic Patients on the Osteogenic Differentiation Potential of Alveolar BMSCs and the Rescue Effect of Metformin: A Bioinformatics-Based Study

Abstract

The success rate of oral implants is lower in type 2 diabetes mellitus (T2DM) patients than in nondiabetic subjects; functional impairment of bone marrow-derived mesenchymal stem cells (BMSCs) is an important underlying cause. Many factors in the blood can act on BMSCs to regulate their biological functions and influence implant osseointegration, but which factors play important negative roles in T2DM patients is still unclear. This study is aimed at screening differentially expressed genes in the blood from T2DM and nondiabetic patients, identifying which genes impact the osteogenic differentiation potential of alveolar BMSCs in T2DM patients, exploring drug intervention regimens, and providing a basis for improving implant osseointegration. Thus, a whole-blood gene expression microarray dataset (GSE26168) of T2DM patients and nondiabetic controls was analyzed. Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) results, differentially expressed genes and signaling pathways related to BMSC osteogenic differentiation were screened, and major risk genes were extracted based on the mean decrease Gini coefficient calculated using the random forest method. Bone morphogenetic protein-4 (BMP-4), with significantly low expression in T2DM blood, was identified as the most significant factor affecting BMSC osteogenic differentiation potential. Subsequently, metformin, a first-line clinical drug for T2DM treatment, was found to improve the osteogenic differentiation potential of BMSCs from T2DM patients via the BMP-4/Smad/Runx2 signaling pathway. These results demonstrate that low BMP-4 expression in the blood of T2DM patients significantly hinders the osteogenic function of BMSCs and that metformin is effective in counteracting the negative impact of BMP-4 deficiency.