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

2型糖尿病骨折愈合过程中单核细胞和成骨细胞之间的相互作用

基本信息

批准号：
388929558
负责人：
Privatdozentin Dr. Sabrina Ehnert
金额：
--
依托单位：
Siegfried-Weller-Institut für Unfallmedizinische Forschung (SWI)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/388929558?language=en
关键词：
Interplay between mononuclear osteogenic cells

项目摘要

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.

约。糖尿病是全球最常见的代谢性疾病之一，有2.3亿患者受到影响，且患病率不断上升。除了经典的糖尿病相关合并症（肾功能不全、多发性神经病变、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变化并不均匀。虽然1型糖尿病患者通常表现为骨矿物质密度降低，但2型糖尿病（T2DM）患者的情况更为复杂：T2DM患者产生更多的骨基质，但质量有缺陷。再加上摔倒的风险增加，糖尿病患者骨折的风险增加了6- 12倍。在骨折的情况下，骨整合（骨折的固定和周围软组织的处理）是一个很大的手术挑战。术后患者的活动是困难的，这往往导致骨折愈合时间延长并伴有许多并发症。恢复期差限制了患者的生活质量和生活自理能力。为了提高2型糖尿病患者的骨质量（降低骨折风险）和骨折治疗，了解其潜在机制至关重要。符合标准，在骨外伤后，骨折间隙充满血液并形成血肿。在接下来的炎症期，免疫细胞浸润血肿以吞噬和溶解凝固的血液。在此过程中，细胞分泌细胞因子和生长因子，控制骨细胞的浸润、增殖和分化。这引起了人们对可能影响骨细胞功能的全身血液循环因子的兴趣。在我们的初步工作中，我们编制了T2DM患者的细胞因子谱。与健康对照相比，T2DM患者的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引起的，这是骨折后的一种特征。趋化因子作为免疫细胞的引诱剂和激活剂。由于这些细胞代表了早期骨折血肿的主要细胞比例，它们在骨折愈合中起主导作用。因此，尚不清楚这些趋化因子的表达降低如何影响T2DM患者的骨折愈合。然而，我们的初步研究表明，在2型糖尿病患者中，基于趋化因子表达的减少，更少的单核细胞浸润到骨折血肿中，因此更少的细胞因子分泌，这反过来又损害了骨折愈合。以下拨款提案的重点是验证这一假设并展示其潜在机制。