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.

Effects of metformin on the osteogenesis of alveolar BMSCs from diabetic patients and implant osseointegration in rats

“…BMSCs at passage 4 were used in the present study. The method of BMSC acquisition was the same as that used in our previous study (Liang et al., 2017), and BMSCs were identified (Liang et al., 2020).…”

Is hyperglycemia the only risk factor for implant in type 2 diabetics during the healing period?

“…The fourth‐passage BSCMs were used for subsequent experiments. The cells obtained via the low‐speed drilling technique and cultured via the above method exhibited the characteristics of BMSCs, as found by flow cytometric analysis by the same research group (Liang et al,2020).…”

The Function of Metformin in Aging-Related Musculoskeletal Disorders

“…In addition, BMPs, which are members of the transforming growth factor-β family, play a role in promoting osteogenic differentiation by stimulating DNA synthesis and cell replication. Metformin can play a pro-osteoclastogenic role by activating AMPK/BMP/Smad signaling pathway (Sun et al, 2021) Another similar study also confirms that metformin promotes the osteogenic function of pro-osteoblasts in type 2 diabetic patients through the BMP-4/ Smad/Runx2 axis (Liang et al, 2020). GSK3β can also act as a mediator in the process of metformin-promoted osteoblast differentiation.…”