Cardiovascular calcification is a prominent feature of chronic inflammatory disorders — such as chronic kidney disease (CKD), type 2 diabetes (T2D), and atherosclerosis — that associate with significant morbidity and mortality. The concept that similar pathways control both bone remodeling and vascular calcification is widely accepted, but the precise mechanisms of calcification remain largely unknown. Micro-RNAs (miRNAs) are a large class of evolutionarily conserved, small, endogenous, non-coding RNAs serving as essential post-transcriptional modulators of gene expression that play a crucial role in normal physiology. The central role of microRNAs (miRNA) as fine-tune regulators in the cardiovascular system and bone biology has gained acceptance and has raised the possibility for novel therapeutic targets. Additionally, circulating miRNAs have been proposed as biomarkers for a wide range of cardiovascular diseases, but knowledge of miRNA biology in cardiovascular calcification is very limited. However, we recently provided the first miRNA-dependent mechanism in the progression of vascular calcification by demonstrating that miR-125b dysregulation leads to the transition of human coronary arterial smooth muscle cells (HCASMC) into osteoblast-like cells. Osteogenic transition of HCASMC was induced by osteogenic medium and led to matrix mineralization. Increased expression of miR-125b was time-dependent in HCASMC and diminished during osteogenesis. After 21 days in the osteogenic environment, miR-125b was significantly reduced (-42%) compared with HCASMC cultured in control medium. The expression of two miR-processing enzymes that are essential for SMC function, RNase III endonucleases DICER1 and DROSHA, were reduced in calcified HCASMCs. Furthermore, inhibition of endogenous miR-125b promoted alkaline phosphatase activity and matrix mineralization in vitro. Correspondingly, in vivo observations indicate that miR-125b is decreased in calcified aortas of apolipoprotein-deficient (Apoe) mice fed a high fat diet for 26 weeks compared to those sacrificed after 10 weeks. In silico and expression analyses revealed the osteoblast transcription factor SP7 (osterix) as a target of miR-125b. Our results suggest that miR-125b is involved in vascular calcification in vitro and in vivo, at least partially by targeting SP7. As cardiovascular calcification and bone remodeling share common mechanisms, we need an in-depth understanding of miRNA function and their association with the molecular pathogenesis of osteoporosis and vascular calcification. This knowledge will be critical for the developing of a more specific therapy for cardiovascular calcification that does not adversely affect physiological bone homoeostasis.