Li Ruoyu, Li Wenfeng, Teng Yungshan, Li Runze, Kong Siyi, Chen Xin, Luo Haotian, Chen Danying, Guo Yuqing, Qing Yangqiao, Leong Hio Cheng, Guo Bingyan, Chen Meihan, Pan Zixin, Zheng Shushuo, Deng Yihong, Cao Yang, Zhou Chen, Zou Xuenong, Wang Weicai
Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China.
Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
Biofabrication. 2025 Jan 23;17(2). doi: 10.1088/1758-5090/ada737.
Craniofacial bone defect healing in periodontitis patients with diabetes background has long been difficult due to increased blood glucose levels which cause overproduction of reactive oxygen species (ROS) and a low pH environment. These conditions negatively affect the function of macrophages, worsen inflammation and oxidative stress, and ultimately, hinder osteoblasts' bone repair potential. In this study, we for the first time found that annexin A1 (ANXA1) expression in macrophages was reduced in a diabetic periodontitis (DP) environment, with the activation of the NLRP3/Caspase-1/GSDMD signaling pathway, and, eventually, increased macrophage pyroptosis. Next, we have developed a new GPPG intelligent hydrogel system which was ROS and pH responsive, and loaded with Ac2-26, an ANXA1 bioactive peptide, and osteogenic peptide OGP as well. We found that Ac2-26/OGP/GPPG can effectively reduce ROS, mitigates macrophage pyroptosis via the ANXA1/NLRP3/Caspase-1/GSDMD pathway and enhanced osteogenic differentiation. The effect of Ac2-26/OGP/GPPG in regulation of pyroptosis and bone defect repair was also further validated by animal experiments on periodontitis-induced tooth loss model in diabetic rats. To conclude, our study unveils the effect of ANXA1 on macrophage pyroptosis in periodontitis patients with diabetes, based on which we introduced a promising innovative hydrogel system for improvement of bone defects repair in DP patients via targeting macrophage pyroptosis and enhancing osteogenic potential.
由于血糖水平升高导致活性氧（ROS）过度产生和低pH环境，糖尿病背景下的牙周炎患者颅面骨缺损愈合长期以来一直很困难。这些情况对巨噬细胞的功能产生负面影响，加剧炎症和氧化应激，最终阻碍成骨细胞的骨修复潜力。在本研究中，我们首次发现，在糖尿病性牙周炎（DP）环境中，巨噬细胞中膜联蛋白A1（ANXA1）的表达降低，NLRP3/半胱天冬酶-1/GSDMD信号通路被激活，最终巨噬细胞焦亡增加。接下来，我们开发了一种新的GPPG智能水凝胶系统，该系统对ROS和pH有响应，并负载了ANXA1生物活性肽Ac2-26和成骨肽OGP。我们发现，Ac2-26/OGP/GPPG可以有效降低ROS，通过ANXA1/NLRP3/半胱天冬酶-1/GSDMD途径减轻巨噬细胞焦亡，并增强成骨分化。在糖尿病大鼠牙周炎诱导的牙齿脱落模型上进行的动物实验也进一步验证了Ac2-26/OGP/GPPG在调节焦亡和骨缺损修复方面的作用。总之，我们的研究揭示了ANXA1对糖尿病牙周炎患者巨噬细胞焦亡的影响，在此基础上，我们引入了一种有前景的创新水凝胶系统，通过靶向巨噬细胞焦亡和增强成骨潜力来改善DP患者的骨缺损修复。
