MicroRNA let-7g links foam cell formation and adipogenic differentiation: A key regulator of Paeonol treating atherosclerosis-osteoporosis

High comorbidity rates have been reported in patients with atherosclerosis and osteoporosis, posing a serious risk to the health and well-being of elderly patients. To improve and update clinical practice regarding the joint treatment of these two diseases, the common mechanisms of atherosclerosis and osteoporosis need to be clarified. MicroRNAs (miRNAs), are importance molecules in the pathogenesis of human diseases, including in cardiovascular and orthopedic fields. They have garnered interest as potential targets for novel therapeutic strategies. However, the key miRNAs involved in atherosclerosis and osteoporosis and their precise regulation mechanisms remain unknown. Paeonol (Pae), an active ingredient in Cortex Moutan, has shown promising results in improving both lipid and bone metabolic abnormalities. However, it is uncertain whether this agent can exert a cotherapeutic effect on atherosclerosis and osteoporosis. This study aimed to screen important shared miRNAs in atherosclerotic and osteoporotic complications, and explore the mechanism of the protective effects of Pae against atherosclerosis and osteoporosis in high-fat diet (HFD)-fed ApoE−/− mice. An experimental atherosclerosis and osteoporosis model was established in 40-week-old HFD ApoE−/- mice. Various techniques such as Oil Red O staining, HE staining and micro-CT were used to confirm the co-occurrence of these two diseases and efficacy of Pae in addition to the associated biochemical changes. Bioinformatics was used to screen key miRNAs in the atherosclerosis and osteoporosis model, and gene involvement was assessed through serum analyses, qRT-PCR, and western blot. To investigate the effect of Pae on the modulation of the miR let-7g/HMGA2/CEBPβ pathway, Raw 264.7 cells were cocultured with bone marrow mesenchymal stem cells (BMSCs) and treated with an miR let-7g mimic/inhibitor. miR let-7g identified using bioinformatics was assessed to evaluate its participation in atherosclerosis-osteoporosis. Experimental analysis showed reduced miR let-7g levels in the atherosclerosis-osteoporosis mice model. Moreover, miR let-7g was required for BMSC - Raw 264.7 cell crosstalk, thereby promoting foam cell formation and adipocyte differentiation. Treatment with Pae significantly reduced plaque accumulation and foam cell number in the aorta while increasing bone density and improving trabecular bone microarchitecture in HFD ApoE−/- mice. Pae also increased the level of miR let-7g in the bloodstream of model mice. In vitro studies, Pae enhanced miR let-7g expression in BMSCs, thereby suppressing the HMGA2/CEBPβ pathway to prevent the formation of foam cells and differentiation of adipocytes induced by oxidized low-density lipoprotein (ox-LDL). The study results suggested that miR let-7g participates in atherosclerosis -osteoporosis regulation and that Pae acts as a potential therapeutic agent for preventing atherosclerosis-osteoporosis through regulatory effects on the miR let-7g/HMGA2/CEBPβ pathway to hinder foam cell formation and adipocyte differentiation.