Abstract：
Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.
摘要：
吸烟会破坏骨骼稳态，并成为骨质疏松症发展和进展的独立危险因素。烟草毒素抑制骨髓间充质干细胞(BMSCs)的增殖和成骨分化,促进BMSCs衰老和衰竭，但是具体机制还没有完全理解。在这里，通过腹腔注射香烟烟雾提取物(CSE),成功建立了大鼠和小鼠吸烟相关骨质疏松(SROP)模型,在体内和体外均能显著降低BMSCs的骨密度并诱导衰老和抑制BMSCs的成骨分化。生物信息学分析和体外实验证实，CSE通过氧化应激和抑制线粒体自噬来破坏线粒体稳态。此外，我们发现CSE通过上调磷酸化AKT诱导BMSCs衰老，进而抑制FOXO3a和Pink1/Parkin通路的表达，导致线粒体自噬的抑制和受损线粒体的积累。MitoQ,线粒体靶向抗氧化剂和线粒体自噬激动剂，有效减少CSE诱导的线粒体氧化应激，促进线粒体自噬，显著下调BMSCs衰老标志物的表达，恢复成骨分化，减轻CSE暴露小鼠的骨丢失和自噬水平。总之,我们的结果表明，通过AKT/FOXO3a/Pink1/Parkin轴抑制线粒体自噬引起的BMSCs衰老是吸烟相关性骨质疏松症的关键机制。
