The miR‐193a‐3p‐MAP3k3 Signaling Axis Regulates Substrate Topography‐Induced Osteogenesis of Bone Marrow Stem Cells

Substrate topographical features induce osteogenic differentiation of bone marrow stem cells (BMSCs), but the underlying mechanisms are unclear. As microRNAs (miRNAs) play key roles in osteogenesis and bone regeneration, it would be meaningful to elucidate the roles of miRNAs in the intracellular signaling cascade of topographical cue‐induced osteogenic differentiation. In this study, the miRNA expression profile of the topographical feature‐induced osteogenic differentiation group is different from that of the chemical‐factors‐induced osteogenic differentiation group. miR‐193a‐3p is sensitive to substrate topographical features and its downregulation enhances osteogenic differentiation only in the absence of osteogenesis−inducing medium. Also, substrate topographical features specifically activate a nonclassical osteogenetic pathway—the mitogen‐activated protein kinase (MAPK) pathway. Loss‐ and gain‐of‐function experiments demonstrate that miR‐193a‐3p regulates the MAPK pathway by targeting the MAP3k3 gene. In conclusion, this data indicates that different osteogenic‐lineage‐related intracellular signaling cascades are triggered in BMSCs subjected to biophysical or chemical stimulation. Moreover, the miR‐193a‐3p‐MAP3k3 signaling axis plays a pivotal role in the transduction of biophysical cues from the substrate to regulate the osteogenic lineage specification of BMSCs, and hence may be a promising molecular target for bone regenerative therapies. Topographical feature‐induced bone marrow stem cells (BMSCs) lineage specification is different from that of chemical‐factors‐induced BMSCs lineage specification in terms of microRNA expression. MiR‐193a‐3p‐MAP3k3 signaling axis plays a pivotal role in the transduction of biophysical cues from the substrate to regulate the osteogenic differentiation of BMSCs. As an outlook, when designing implantable biomedical devices or orthopedic substitutes, more attention should be focused on their biophysical properties.