脊柱机械加载调控血管生成和骨重建治疗骨质疏松的机制研究

Osteoporosis is a systemic disease with high morbidity, it’s important to explore non-pharmacological treatment and underlying mechanism due to the limitation of existing osteoporosis medicine. Our previous studies showed that pulsating joint mechanical loading such as elbow joint and knee joint loading could promote angiogenesis and bone growth, and accelerate healing of bone injury. Angiogenesis is necessary for fracture healing and osteonecrosis treatment, but the role of angiogenesis in osteoporosis treatment and bone remodeling is unclear. This project plans to investigate the mechanism of osteoporosis therapy by pulsating mechanical loading on spine. We hypothesis that osteoporosis is a bone loss disease associated with reduction of bone blood perfusion and vascular number/volume, and spine mechanical loading inhibits osteoclast development and promotes osteoblast differentiation in the treatment of osteoporosis through regulating angiogenesis and bone remodeling by SUMOylation of Wnt signaling pathway. This project will adopt the methods of animal experiment, histology, cytology and molecular biology to assess that mechanical loading can affect the stem cells differentiation, increase bone mass and bone mineral density by small in situ strain. We will also evaluate that mechanical loading promotes angiogenesis and regulates bone remodeling including suppressing bone resorption and accelerating bone formation. The effect of SUMOylation on Wnt signaling pathway will be illustrated. This project provides a potential approach for treatment of osteoporosis by exploring the relationship between angiogenesis and bone reconstruction.

骨质疏松是一种致残率高的全身性疾病，鉴于药物治疗的限制性，研究非药物性治疗方法及机制具有重要意义。前期研究表明，脉冲性关节机械加载可以促进血管生成和骨生长，加速骨损伤愈合。血管生成在骨折修复、骨坏死治疗中是必不可少的，但骨质疏松治疗中血管生成的作用尚不明确，与骨重建的关系有待探讨。本项目将阐明对脊柱进行脉冲性机械加载治疗骨质疏松的机制。我们提出假设：骨质疏松是一种骨量减少伴随骨血供减少/血管减少的疾病，机械加载可能通过SUMO化激活Wnt信号通路调控血管生成和骨重建，抑制破骨细胞发育和促进成骨细胞分化治疗骨质疏松。拟采用动物实验、组织学、细胞学和分子生物学等手段验证机械加载通过机械应力调控干细胞分化，增加骨量和骨密度；阐明机械加载促进血管生成、改善骨重建（抑制骨吸收和促进骨形成）的机制；明确SUMO化影响Wnt信号通路的作用。本研究通过探索血管生成与骨重建的关系，为骨质疏松治疗提供新方法。

骨质疏松是我国老龄化社会面临的严重危害公共健康的全身性疾病，非药物治疗方法及机制有待研究。血管生成在骨折修复、骨坏死治疗中非常重要，但其在骨质疏松发生发展和治疗中的作用尚不明确。我们的研究证实骨质疏松是一种骨量减少伴随骨微血管减少的疾病。本项目中，我们通过鼠尾悬吊和卵巢去势动物模型、骨密度测量和micro-CT等手段验证脊柱机械加载可以增加骨量和骨密度、改善骨微结构；组织学染色和墨汁灌注实验证实机械加载促进体内骨微血管新生、成骨细胞增多，并抑制体内破骨细胞活性；在体内和体外同时探索机械加载通过调节血管生成和骨重建，从而减少骨丢失的机制；另外利用细胞学和分子生物学技术阐明SUMO和Wnt信号通路参与机械加载调控血管生成与骨重建的机制。总之，这些结果表明脊柱机械加载作为一种物理康复的非药物治疗方法，通过调控血管生成和骨重建、抑制破骨细胞发育和促进成骨细胞分化治疗骨质疏松的机制。