基于氧化应激-自噬探讨酒精性骨重构的机制及中药干预

The Lancet study shows that alcohol use can cause a lot of damage and is the seventh leading risk factor for death. Long-term alcohol intake can lead to structural trabecular bone structure, decreased biomechanical properties, and even osteonecrosis. Alcoholic bone remodeling is characterized by abnormal bone and bone mass. It is a comprehensive reflection of abnormal bone metabolism caused by alcohol-induced bone tissue cells, which is characterized by abnormal osteogenesis/adipogenic differentiation of bone marrow mesenchymal stem cells. The main bone of the liver is the main bone of the kidney. The wine is the evil of dampness and heat. It is easy to enter the collaterals and hurt the blood. Chinese medicine believes that alcoholic bone remodeling is the main pathogenesis of kidney deficiency and blood stasis, and it is the main method of tonifying kidney and promoting blood circulation. In the previous experiments, alcoholic bone injury was evaluated from the perspectives of biomechanics, pathology and Micro-CT. It is necessary to further explore the relationship between oxidative stress-autophagy and osteogenesis/adipogenic disorder caused by alcohol stimulation at the level of animal, cell and molecular regulation mechanisms. The differential expression of genes induced by alcohol-induced bone marrow mesenchymal stem cells was screened, and the key regulatory genes of oxidative stress-autophagy were screened. The relationship between oxidative stress-autophagic flow and osteogenesis/adipogenesis was investigated by gene overexpression/low expression; confirmation was based on Traditional Chinese medicine (Bone tonifying and blood-activating method) (Bone sclerotium, Salvia miltiorrhiza, Rhizoma Chuanxiong) promotes bone/inhibition of adipogenic differentiation to interfere with alcoholic bone remodeling, providing a theoretical basis for clinical intervention in alcoholic bone disease.

《柳叶刀》研究表明，酒精使用可导致诸多损害，是导致死亡的第七大风险因素。长期酒精摄入可导致骨小梁结构紊乱、生物力学性能下降，甚至骨坏死。酒精性骨重构以骨质和骨量异常为特征，是酒精诱导骨组织细胞异常代谢而致骨稳态失衡的综合反映，表现为骨髓间充质干细胞成骨/成脂分化功能异常等。肝主筋肾主骨，酒乃湿热之邪，易入络伤血，中医认为酒精性骨重构以肾虚血瘀为主要病机，以补肾活血法主之。前期实验从生物力学、病理、Micro-CT等角度评价了酒精性骨损伤，需进一步在动物、细胞和分子调控机制水平探究酒精刺激导致氧化应激-自噬与成骨/成脂紊乱关系。明确酒精诱导骨髓间充质干细胞基因差异表达，筛选氧化应激-自噬关键调控基因；通过基因过表达/低表达等技术探讨氧化应激-自噬流与成骨/成脂关系；确证基于“补肾活血法”中药（骨碎补、丹参、川芎）促成骨/抑成脂分化干预酒精性骨重构的机制，为临床干预酒精性骨病提供理论依据。

酒精性骨重构以全身骨质和骨量异常为特征，是酒精诱导骨组织细胞异常代谢而导致骨稳态失衡的综合反映，直接或间接导致骨髓基质干细胞、成骨细胞、破骨细胞、骨细胞及髓内细胞活性和功能异常，是酒精性骨坏死、酒精性骨质疏松症等的共同核心病理过程，属代谢性筋骨骱病范畴。本研究系统阐明了酒精通过激活氧化应激和干扰细胞自噬介导了酒精性骨重构的发生和发展，研究确实了基于“补肾活血”类方药(骨碎补、丹参、川芎及其单体化合物等)及接骨木等靶向氧化应激干预酒精性骨重构的潜在机制。在动物、细胞和分子调控机制等水平探究了酒精/中药介导氧化应激-自噬调控骨髓基质干细胞分化紊乱关系，丰富了“肾主骨生髓”的科学内涵。本研究初步构建了“酒毒三伤”（首伤胃肠之腑，中伤肝肾之脏，终伤筋骨之髓）病机体系、“肠-骨”轴病证传变体系和“异病同治”、“同病异治”视域下酒精性筋骨骱病论治体系，互为补充，互为所用，为临床防治酒精性骨病提供参考和依据。