Hyperlipidemia impairs bone repair and regeneration via miR-193a-3p/STMN1/PI3K/Akt axis

Hyperlipidemia, a metabolic disease characterized by excessive blood lipid, disturbs bone metabolism by shifting cell fate of bone marrow stromal cells (BMSCs) towards adipogenic differentiation, thus resulting in poor bone regeneration and osseointegration of implants. Among numerous factors affecting hyperlipidemic bone metabolism, non-coding RNAs play an essential role in post-transcriptional regulation. Our previous study has shown that miR-193a-3p levels were elevated in hyperlipidemia, which hindered implant osseointegration and BMSCs function. However, the downstream targets and pathways of miR-193a-3p warrant further investigation. In this study, we identified STMN1 as the target of miR-193a-3p by miRNA databases and validated their interaction through dual luciferase reporter assays. Models of hyperlipidemia were established in vitro using a high-fat medium and in vivo with a high-fat diet to study these molecular interactions. Besides, miRNA array and PCR analyses confirmed the level of miR-193a and STMN1 in both rats with hyperlipidemia and high-fat-cultured BMSCs. Calvarial defects were used to evaluate STMN1's impact on bone repair and regeneration. As a result, miR-193a-3p levels were highly elevated in hyperlipidemic conditions, whereas the STMN1 levels were reduced sharply. The elevated miR-193a targeted STMN1 and disabled it from activating the PI3K/Akt pathway, thus resulting in delayed bone repair and poor bone regeneration. Additionally, common lipid-lowering drug simvastatin blunted hyperlipidemia's adverse effect on this axis. Our findings underscore the miR-193a-3p/STMN1/PI3K/Akt axis as a novel and promising therapeutic target for hyperlipidemic osteopenia, offering insights into the molecular mechanisms underlying bone metabolism disorders in hyperlipidemia and paving the way for innovative treatments.