AdipoRon在改善糖尿病患者牙种植体骨整合能力的相关机制研究

Diabetes is considered as one of the risk factors for dental implant therapy. Hyperglycemia leads to increased secretion of TNF-alpha in macrophages in white adipose tissues, down-regulateing bone cell biology and thus decreases the osseointegration of the implant-bone interface. Our previous studies showed that TNF-alpha caused bone resorption in tissue-engineered cartilage, and shall lead to peri-implant bone resorption. Adiponectin is effective in inhibiting the secretion of proinflammatory cytokines like TNF-alpha, down-regulating osteoclastogenesis, promoting osteogenesis, while it is not suitable for clinical application. AdipoRon, an oral adiponectin receptor agonist, effectively in reducing plasma glucose in diet-induced obesity mice, has potential in clinical use. However, the effects of AdipoRon on osseointegration in patients with diabetes are unknown. Thus, hypothesis is proposed that AdipoRon can improve the osseointegration of dental implants in diabetic patients by promoting osteogenesis, inhibiting osteoclastogenesis, and decrease the secretion of proinflammatory cytokines. We intend to validate our hypothesis by using various kinds of techniques as bioinformatics analysis, protein co-immunoprecipitation and RNA interferences and provide new avenues for improving the osseointegration of dental implant in diabetic patients.

糖尿病是影响种植治疗成功的危险因素之一，高血糖会上调脂肪组织内巨噬细胞促炎因子TNF-alpha的分泌，影响骨细胞的功能，进而影响种植体-骨界面的骨整合，因此患者血糖控制不佳会影响种植治疗效果。我们前期研究发现，TNF-alpha会导致软骨工程骨的吸收，即种植体周骨吸收。有文献报道脂联素能有效抑制巨噬细胞促炎因子TNF-alpha的分泌、抑制破骨分化、促进成骨分化，但因种种原因，脂联素不适临床使用。AdipoRon，一种可以口服的脂联素受体激动剂，可有效降低饮食诱导肥胖动物的血糖水平，有很大的临床使用前景。然AdipoRon对糖尿病患者种植体骨整合影响尚未知。因此，我们提出假说：AdipoRon能通过抑制促炎因子的释放，促进成骨、抑制破骨从而改善糖尿病患者的牙种植体骨整合能力。本研究拟从分子、细胞和动物水平验证该假说，为提高糖尿病患者种植体骨整合能力提供新途径。

未受良好血糖控制的糖尿病是影响牙科种植治疗成功率的危险因素之一。高糖血症会促进破骨细胞分化，抑制成骨分化，导致破骨-成骨骨稳态失衡，进而影响种植体-骨界面的骨结合。AdipoRon，一种可以口服有效的脂联素受体激动剂，近期被合成后发现可有效降低饮食诱导肥胖动物的血糖水平和糖尿病相关并发症。我们通过研究，发现AdipoRon及其类似物AdipoAI在高糖环境下对破骨细胞分化的抑制作用，并初步分析其作用机制，发现与促进细胞的自噬有关；同时在小鼠体内，发现AdipoRon可缓解糖尿病牙周炎所致的牙槽骨骨吸收。另一项研究发现，AdipoRon可以通过抑制糖尿病小鼠股骨种植体周RANKL/OPG的表达，促进植体周的骨质沉积。此外，一项研究发现，AdipoRon还可通过扩大SDF-1的趋化梯度，促进骨髓间充质细胞的迁移，改善糖尿病小鼠颅骨缺损的骨修复。上述我们已发表的研究表明，AdipoRon可以从抑制破骨、促进成骨分化方面改善糖尿病相关的钛种植体的骨结合，为以后AdipoRon的临床应用提供了一定的佐证，但是关于其在高糖环境下既抑制破骨细胞分化、又促进成骨细胞分化的直接分子机制还需要进一步的研究。