游离泛素通过介导内皮细胞EndMT调控异位骨化形成的作用与分子机制研究

Heterotopic ossification (HO) is an inflammatory related disease, which could result in dysfunction of limb joint and subsequent difficulties on work and life. In current clinical practice, HO is one of the treatment problem, and the pathophysiologic mechanism of HO is still unclear. Our preliminary results showed that the free ubiquitin was significantly elevated in patients with HO, and treatment of free ubiquitin could affect the endothelial mesenchymal transition and osteogenesis process. The extracellular ubiquitin could regulate inflammatory reaction by forming compound with CXCR4, which could be related to the formation of HO. Thus, effective intervention and regulation of endothelial mesenchymal transition could be the treatment window for reverse and early handling of HO. Based on these results, our proposal plan to investigate the mechanisms involved in the free ubiquitin mediated protective effects from the view of CXCR4 receptor of heterotopic ossification by multiple molecular cellular techniques and experimental techniques. The fulfill of this project could be helpful to enhance the recognition on the molecular mechanism of heterotopic ossification, identify the novel molecule involved in the heterotopic ossification regulation, elucidate the possible regulatory way, thereby provide novel therapeutic target for the treatment of heterotopic ossification.

异位骨化作为一种炎症诱发的疾病，可以导致肢体关节功能的丧失，造成患者工作和生活的困难，目前成为临床治疗的难点，对异位骨化的病理生理机制的认识也尚不明确。申请人前期的结果提示异位骨化病人游离泛素水平显著升高，而游离泛素处理能够抑制异位骨形成主要细胞来源-内皮细胞的内皮间质转化及成骨分化的过程。胞外游离泛素能够通过与CXCR4形成复合物对炎症反应发挥调控效应，从而可能参与异位骨化的形成过程。因此我们设想通过游离泛素有效的干预和调控内皮细胞的内皮间质转化过程可能是逆转和早期介入异位骨化治疗的重要切入点。课题在前期研究的基础上，拟通过多种分子细胞生物学及实验动物学手段对游离泛素通过与CXCR4受体结合参与到异位骨化中的机制研究进行深入研究。此项目的顺利实施，将有助于增强人们对于异位骨化发生发展机制的认识，发现异位骨化新的调控分子并揭示其调控机理，为临床异位骨化的药物治疗提供新的思路。

研究和明确异位骨化的病理生理机制对于异位骨化的治疗意义重大。异位骨的内皮细胞来源属性及内皮间质转化过程存在于异位骨的形成过程中，因此，有效的干预和调控内皮间质转化过程可能是逆转和早期介入异位骨化治疗的重要切入点。本课题主要研究游离泛素（UB）在EndMT、成骨分化以及异位骨化骨形成中的作用与机制。研究结果表明创伤性异位骨化病人游离泛素水平显著升高，而游离泛素处理能够显著抑制异位骨形成主要细胞来源-内皮细胞的内皮间质转化（EndMT）及体外诱导成骨分化的过程，进一步通过体内小鼠股骨骨折模型证明了游离泛素能够显著抑制体内成骨分化，从而具有运用于异位骨化的治疗的潜力，为创伤性异位骨化的防治提供了新的思路和治疗策略。