Background <p>Mandibular bone marrow stem cells (BMSCs) from patients with type 2 diabetes mellitus (T2DM) have poor osteogenic differentiation capacity. Elucidating the molecular mechanisms by which circular RNAs (circRNAs) play specific roles in T2DM will reveal new diagnostic biomarkers and therapeutic targets.</p> Methods <p>BMSCs with different circ_0054633 expression levels were generated. Furthermore, alkaline phosphatase (ALP) activity, alizarin red staining (ARS), and transplantation of HA/tricalcium phosphate into BMSCs were performed to detect the osteogenic effects of different levels of circ_0054633 expression in BMSCs in vivo and in vitro.</p> Results <p>In this study, we identified 80 differentially expressed circRNAs in jawbone-derived BMSCs from patients with T2DM. Notably, significant downregulation of circ_0054633 promoted the osteogenic differentiation of these cells in vitro and in vivo. Mechanistically, circ_0054633 acts as a miRNA sponge; specifically, it actively regulates the expression of RUNX2 by sponging miR-590-3p and thus promoting the osteogenic differentiation of the BMSCs. In addition, we found that circ_0054633 was a direct transcriptional target of RUNX2. RUNX2 overexpression activated the circ_0054633 promoter and promoted the generation of nuclear circ_0054633, whereas RUNX2 knockdown abrogated the osteogenic role of circ_0054633 and formed a circ_005463/miR-590-3p/RUNX2 positive feedback loop.</p> Conclusions <p>Our results suggest that the circ_0054633/miR-590-3p/RUNX2 positive feedback loop promotes the osteogenic differentiation of BMSCs and is expected to be a potential biomarker and therapeutic target for bone regeneration in T2DM.</p>