Interplay between mononuclear and osteogenic cells during fracture healing in type 2 diabetics

用约糖尿病是世界上最常见的代谢紊乱之一，受2.3亿患者影响，患病率不断增加。除了典型的糖尿病相关合并症（肾功能不全、多发性神经病、视力丧失等）外，糖尿病引起的影响骨骼系统的变化越来越重要。有趣的是，糖尿病患者的骨结构并没有发生均匀的改变。虽然1型糖尿病患者经常显示骨矿物质密度降低，但2型糖尿病（T2 DM）的情况更为复杂：T2 DM患者产生更多的骨基质，但质量有缺陷。再加上跌倒的风险增加，糖尿病患者的骨折风险增加了6- 12倍。在骨折的情况下，接骨术（骨折的固定和周围软组织的处理）是一个很大的手术挑战。术后患者活动困难，常导致骨折愈合时间延长，并发症多。2型糖尿病患者骨折后的恢复期不佳，严重影响了患者的生活质量和自理能力，因此，了解其发生机制，对于改善T2 DM患者的骨质量（降低骨折风险）以及进行骨折治疗至关重要。符合骨创伤后立即出现的标准，骨折间隙充满血液并形成血肿。在随后的炎症阶段，免疫细胞浸润血肿，以吞噬细胞并溶解凝固的血液。在这样做的同时，细胞分泌细胞因子和生长因子，其控制骨细胞的以下浸润、增殖和分化。这引起了对可能影响骨细胞功能的全身性血液循环因素的兴趣。在我们的初步工作中，我们编制了T2 DM患者的细胞因子谱。与健康对照相比，T2 DM患者显示CCL和CXCL趋化因子水平显著降低。这些趋化因子的表达通常是由缺氧诱导的，缺氧是骨折后的特征性条件。在那里，趋化因子充当免疫细胞的吸引剂和激活剂。由于这些细胞代表了早期骨折血肿的主要细胞比例，因此它们在骨折愈合中起主导作用。因此，目前尚不清楚这些趋化因子的表达减少如何影响T2 DM患者的骨折愈合，但我们的初步工作表明，在T2 DM患者中，基于趋化因子表达减少，较少的单核细胞浸润骨折血肿，因此分泌较少的细胞因子，这反过来又损害了随后的骨折愈合。以下资助提案的重点是验证这一假设，并展示潜在的机制。

With approx. 230 million patients affected and a constantly increasing prevalence, diabetes mellitus is one of the most common metabolic disorders worldwide. Alongside the classical diabetes associated comorbidities (renal insufficiency, polyneuropathies, loss of vision, etc.) diabetes-induced changes affecting the skeletal system gain more and more importance. Interestingly, bone structure is not homogeneously altered among diabetics. While type 1 diabetics often display reduced bone mineral densities, the condition is more complex for type 2 diabetics (T2DM): T2DM patients produce more bone matrix, however with a defective quality. In combination with an increased risk to tumble this increases the fracture risk in diabetics by 6- to 12-fold.In case of a fracture the osteosynthesis (fixation of the fracture and handling of the surrounding soft tissue) represents a big surgical challenge. Post-operative mobilization of the patients is difficult, which often results in a prolonged fracture healing with lots of complications. The poor convalescence limits the patients quality of life and self-dependence.In order to improve bone quality (reducing the fracture risk) as well as the fracture treatment in T2DM patients, fundamental knowledge of the underlying mechanisms is essential. Conforming to standards immediately after trauma of the bone, the fracture gap is filled with blood and a hematoma forms. In the following inflammatory phase immune cells infiltrate the hematoma in order to phagocyte and lyse the coagulated blood. While doing so, the cells secrete cytokines and growth factors, which control the following infiltration, proliferation and differentiation of bone cells. This raises the interest in systemic, blood circulating factors which might affect bone cell function. In our preliminary work we compiled a cytokine profile of T2DM patients. In comparison to healthy controls T2DM patients display significantly reduced levels of CCL and CXCL chemokines. Expression of these chemokines is typically induced by hypoxia, a condition characteristic after fracture. There the chemokines act as attractant and activator for immune cells. As these cells represent the main cellular proportion of the early fracture hematoma, they play a leading role in fracture healing. Thus it is not yet conceivable how the reduced expression of these chemokines affects fracture healing in T2DM patients.However, our preliminary work suggests that in T2DM patients based on the reduced expression of chemokines less mononuclear cells infiltrate the fracture hematoma, consequently less cytokines are secreted which in turn impairs the following fracture healing. Focus of the following grant proposal is to verify this hypothesis and to demonstrate the underlying mechanisms.