Abstract：
Atrophic nonunion (AN) is a complex and poorly understood pathological condition resulting from impaired fracture healing. Advanced glycation end products (AGEs) have been implicated in the pathogenesis of several bone disorders, including osteoporosis and osteoarthritis. However, the role of AGEs in the development of AN remains unclear. This study found that mice fed a high-AGE diet had a higher incidence of atrophic nonunion (AN) compared to mice fed a normal diet following tibial fractures. AGEs induced two C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, which were necessary for the development of AN in response to AGE accumulation. Feeding a high-AGE diet after fracture surgery in CtBP1/2-/- and RAGE-/- (receptor of AGE) mice did not result in a significant occurrence of AN. Molecular investigation revealed that CtBP1 and CtBP2 formed a heterodimer that was recruited by histone deacetylase 1 (HDAC1) and runt-related transcription factor 2 (Runx2) to assemble a complex. The CtBP1/2-HDAC1-Runx2 complex was responsible for the downregulation of two classes of bone development and differentiation genes, including bone morphogenic proteins (BMPs) and matrix metalloproteinases (MMPs). These findings demonstrate that AGE accumulation promotes the incidence of AN in a CtBP1/2-dependent manner, possibly by modulating genes related to bone development and fracture healing. These results provide new insights into the pathogenesis of AN and suggest new therapeutic targets for its prevention and treatment.
摘要：
萎缩性不愈合（AN）是一种复杂且鲜为人知的病理状况，由骨折愈合受损引起。晚期糖基化终产物（AGEs）与几种骨骼疾病的发病机理有关。包括骨质疏松症和骨关节炎。然而,AGEs在AN发展中的作用尚不清楚。这项研究发现，与胫骨骨折后正常饮食的小鼠相比，高AGE饮食的小鼠萎缩性骨不连（AN）的发生率更高。AGEs诱导两个C端结合蛋白（CtBP），CtBP1和CtBP2是响应AGE积累而发展AN所必需的。CtBP1/2-/-和RAGE-/-（AGE受体）小鼠骨折手术后喂养高AGE饮食并未导致AN的明显发生。分子研究表明，CtBP1和CtBP2形成了一个异二聚体，该二聚体被组蛋白脱乙酰酶1（HDAC1）和runt相关转录因子2（Runx2）募集以组装复合物。CtBP1/2-HDAC1-Runx2复合物负责下调两类骨发育和分化基因，骨形态发生蛋白(BMPs)和基质金属蛋白酶(MMPs)。这些发现表明，AGE积累以CtBP1/2依赖性方式促进AN的发生，可能通过调节与骨发育和骨折愈合相关的基因。这些结果为AN的发病机制提供了新的见解，并为其预防和治疗提供了新的治疗靶点。
