Sema3A通过β-catenin/Smad4调控骨胶原酶促交联对2型糖尿病骨质量的影响

Type 2 diabetes leads to decreased bone quality, but the mechanism is unclear. Collagen enzymatic cross-links is an important factor in maintaining bone quality. Recent studies have found that collagen enzymatic cross-links is reduced and lysine oxidase (LOX) is a key regulator for collagen enzymatic cross-links in type 2 diabetes. We have found a decreased expression of LOX in osteoblasts under a high-glucose environment. The results have also shown a decreased expression of Sema3A accompanied by inhibition of the β-catenin pathway. In addition, treatment with exogenous Sema3A enhances the expression of LOX and improves the bone quality in diabetes, but the mechanism is unclear. The Smad4 pathway is a key pathway for the regulation of the expression of LOX. Recent studies have found that the transcription of LOX is regulated by β-catenin, suggesting that β-catenin participates in LOX regulation probably via the Smad4 pathway. Accordingly, we hypothesize that Sema3A regulates LOX expression through the β-catenin / Smad4 pathway. We will use gene editing, nano-targeting, co-immunoprecipitation and other techniques to elucidate the role and mechanism by which Sema3A regulates LOX expression in the high glucose environment. The results may help to identify therapeutic targets for decreased bone quality in type 2 diabetes.

2型糖尿病导致骨质量下降，但机制未明。胶原酶促交联是维持骨质量的重要因素，研究发现2型糖尿病胶原酶促交联明显减少，而赖氨酸氧化酶（LOX）是其关键调节酶。我们发现高糖环境成骨细胞LOX表达下降，且伴Sema3A表达下降和β-catenin通路被抑制；给予外源Sema3A可增加LOX表达，逆转糖尿病导致的骨质量下降，但具体机制不清。Smad4通路是LOX表达的关键途径，最新研究发现LOX在核内调节靶基因的转录过程受β-catenin调节，提示β-catenin可能通过Smad4通路参与LOX调节。据此提出 “Sema3A通过β-catenin/Smad4途径调控LOX表达”的假说。本研究拟通过基因编辑、纳米靶向、免疫共沉淀等技术，从分子、细胞和动物整体水平，阐明高糖环境下β-catenin/Smad4在Sema3A调节LOX表达中的作用及其机制，以期为2型糖尿病骨质量下降的治疗提供新思路。

内容获取失败，请点击重试