Shang Jiaming, Li Zechuan, Ma Anquan, Zhu Tiantian, Ma Gaoqiang, Gui Houda, Ren Huiping, Sun Baiyu, Wang Wenhao, Wang Xi, Liu Chenghang, Li Chuanhua, Wang Zhifeng, Lan Jing
Department of Prosthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China.
Department of Prosthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China; National Center for Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices and Beijing Key Laboratory of Digital Stomatology and National Health Commission Key Laboratory of Digital Technology of Stomatology, 100081 Beijing, China; Institute of Advanced Clinical Medicine, Peking University, 100191 Beijing, China.
Biochem Pharmacol. 2025 Feb;232:116693. doi: 10.1016/j.bcp.2024.116693. Epub 2024 Dec 3.
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.
高脂血症是一种以血脂过高为特征的代谢性疾病，它通过使骨髓间充质干细胞（BMSCs）的细胞命运向脂肪生成分化转变来干扰骨代谢，从而导致骨再生不良和植入物的骨整合不佳。在影响高脂血症骨代谢的众多因素中，非编码RNA在转录后调控中起着至关重要的作用。我们之前的研究表明，高脂血症中miR-193a-3p水平升高，这阻碍了植入物的骨整合和BMSCs功能。然而，miR-193a-3p的下游靶点和途径仍有待进一步研究。在本研究中，我们通过miRNA数据库鉴定出STMN1是miR-193a-3p的靶点，并通过双荧光素酶报告基因检测验证了它们之间的相互作用。使用高脂培养基在体外建立高脂血症模型，并在体内使用高脂饮食来研究这些分子相互作用。此外，miRNA阵列和PCR分析证实了高脂血症大鼠和高脂培养的BMSCs中miR-193a和STMN1的水平。使用颅骨缺损来评估STMN1对骨修复和再生的影响。结果，在高脂血症条件下，miR-193a-3p水平显著升高，而STMN1水平急剧降低。升高的miR-193a靶向STMN1并使其无法激活PI3K/Akt途径，从而导致骨修复延迟和骨再生不良。此外，常用的降脂药物辛伐他汀减弱了高脂血症对该轴的不良影响。我们的研究结果强调了miR-193a-3p/STMN1/PI3K/Akt轴是高脂血症性骨质减少的一个新的且有前景的治疗靶点，为深入了解高脂血症中骨代谢紊乱的分子机制提供了见解，并为创新治疗铺平了道路。
