氧化应激/FOXOs/RUNX2通路在老年骨质疏松发生中的作用及机制研究

氧化应激（OS）能够抑制成骨细胞骨形成，但相关分子机制尚有待进一步阐明。成骨细胞过表达Runx2可抑制其成熟分化，导致矿化障碍，骨形成减少。FOXOs是OS应答转录因子，同时对成骨细胞和骨形成发挥重要调控作用。有证据显示FOXOs可能影响成骨细胞Runx2的表达。我们的前期研究表明，老年骨质疏松小鼠（OS状态）骨组织Runx2表达升高；体外H2O2干预在抑制成骨细胞矿化的同时显著上调成骨细胞Foxo1和Runx2的表达。据此我们提出，OS可能通过FOXOs途径促进成骨细胞Runx2表达，进而抑制成骨细胞骨形成，导致骨质疏松。本研究选用老年骨质疏松小鼠模型，结合体外成骨细胞培养，深入研究OS对Runx2的调控机制，明确FOXOs/Runx2是否介导OS对成骨细胞骨形成的抑制及具体分子机制。本项目的开展有助于进一步揭示老年骨质疏松症的发病机理，为骨质疏松的防治提供新的线索和理论依据。

Studies showed that oxidative stress can inhibit osteoblasts bone formation, but the molecular mechanism is still unclarified. Overexpressing of Runx2 in osteoblasts inhibits osteoblasts maturation and leads to decreased bone formation and defective mineralization. FOXOs are important oxidative stress-response transcription factors and play an important role in regulating osteoblasts and bone formation. There is evidence indicating a direct interaction of FOXO1 with the Runx2 promoter, at a specific stage of osteoblasts differentiation. Our preliminary data indicated the up-regulation of Runx2 in senile osteoporotic mice femur. In vitro treatment with H2O2 inhibited mineralization of osteoblasts, whilst expression of Foxo1 and Runx2 in osteoblast was significant increased. Based on it, we hypothesize that oxidative stress could induce Runx2 expression via FOXOs in osteoblasts, and further inhibits bone formation. We will employ aging mice model and osteoblasts culture, through targeted in vivo and in vitro studies, to investigate the effect of oxidative stress on Runx2 expression and to explore whether FOXOs/Ruxn2 mediated regulation of osteoblast function by oxidative stress and further, the molecular mechanism involved. This study will help to reveal the role of oxidative stress in age-related bone loss and senile osteoporosis and may present a novel strategy for prevention and therapy of osteoporosis.