镁离子通过HIF-1α信号通路双向调节骨形成/骨吸收促进骨质疏松性骨折愈合的机制研究

It has been demonstrated that the insufficient capacity of intramembranous osteogenesis and endochondral ossification or accompanied with excessive remodeling ascribed to increased osteoclast activity are the key factors that result in reduced healing capacity of osteoporotic fracture (OPF). Our previous research indicated magnesium-based implant could increase bone regeneration rate and improve bone quality during OPF healing process via enhancing cartilage formation in endochondral ossification and suppressing osteoclastogenesis in callus remodeling, but until now, the mechanism is not clear. Therefore, the magnesium ion was selected as research object in current project to explore the influence of magnesium ion on the function of bone marrow mesenchymal stem cells under osteogenesis differentiation and chondrogenic differentiation and bone marrow mononuclear cells under osteoclast differentiation in different concentration of oxygen environment in vitro. And the deep correlation between cell HIF-1α signaling pathway and magnesium ion will be verified. In vivo, a biodegradable magnesium-based implant (Mg/Co/CaP) integrated with the ionic Co2+ to chemically induce HIF-1α to promote a hypoxia-like response was constructed. Through dynamically observing the changes of HIF-1α signaling pathway related gene and protein expression in fracture fragments and bone formation and resorption activity to clarify the mechanism of magnesium ion promoting OPF healing via HIF-1α signaling pathway. The completion of current study will provide a new perspective and method for the research and treatment of OPF.

膜内成骨和软骨内成骨能力不足，或伴有破骨细胞功能活跃导致的骨痂过度改建，是引起骨质疏松性骨折（OPF）修复能力降低的关键因素。研究发现，镁合金内植物修复绝经后骨质疏松大鼠股骨骨折，可以促进软骨内成骨过程中新生软骨的形成并抑制骨痂改建期破骨细胞生成，加速骨折愈合并提高骨折愈合质量，但其机制尚未明确。为此，本项目选择镁合金降解产生的镁离子作为研究对象，探明镁离子在体外不同氧气环境下对骨髓间充质干细胞成软骨、成骨分化及骨髓单核细胞破骨分化功能的影响，及与HIF-1α信号通路的相关性；通过设计制备可调控HIF-1α信号通路的镁基内植物Mg/Co/CaP修复大鼠OPF，动态观察骨折部位HIF-1α信号通路相关基因和蛋白表达水平的改变，及骨形成和骨吸收活性的变化，阐明镁离子通过HIF-1α信号通路促进OPF愈合的机制。研究的完成可能为OPF的研究及治疗提供一种崭新的思路与方法。

成骨能力不足，骨形成减弱，以及破骨细胞功能活跃导致的骨痂过度改建、骨痂力学性能降低，是引起骨质疏松性骨折延迟愈合或低质量愈合的主要原因。镁合金材料具有双向调节成骨/破骨分化的作用，在骨修复领域应用前景广阔。我们将镁合金材料植入绝经后骨质疏松大鼠体内修复股骨干骨折，研究发现镁合金可以促进大鼠骨质疏松性骨折愈合，提升骨折愈合质量。在骨质疏松骨折愈合过程中，镁合金通过HIF-1α信号通路调控软骨内成骨过程中的胶原代谢和血管化，在骨折愈合的早期可以明显地促进软骨骨痂的生成和矿化，加速骨折愈合进程；在骨折愈合晚期可以有效地抑制绝经后大鼠过度活跃的破骨细胞活性，避免新生骨痂的过度改建，提升骨折愈合质量，发挥双向调节骨形成和骨吸收的生物学功能。镁合金植入体内后，通过增加成骨细胞数量、提升骨组织矿化沉积率和骨形成率，对全身骨稳态的调节具有正性作用，可以局部延缓或逆转骨质疏松性骨量丢失，有效提升膝关节周围骨组织骨量。综上，本研究阐明了镁合金材料通过HIF-1α信号通路促进骨质疏松性骨折愈合的新机制，为骨质疏松性骨折的研究及治疗提供一种崭新的思路与方法。