Huang Jiao, Wang Lin, Tian Weidong
State Key Laboratory of Oral Disease, Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China.
National Engineering Laboratory for Oral Regenerative Medicine, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Int J Nanomedicine. 2021 May 7;16:3161-3172. doi: 10.2147/IJN.S305361. eCollection 2021.
There is no definitive treatment for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Small extracellular vesicles derived from adipose tissue (sEV-AT) have been proved efficient at promoting tissue regeneration. The aim of this study was to evaluate the effects of sEV-AT administration on BRONJ-like lesions in rats.
Zoledronate (Zol) and dexamethasone (Dex) were subcutaneously administered to create a BRONJ rat model. Rats were randomly divided into three groups: 1) Control; 2) Zol+Dex; 3) sEV-AT. The maxillary left first molars were extracted two weeks after the first administration. In the sEV-AT group, sEV-AT were given intravenously every three days right after tooth extraction. We preformed occlusal view images, microcomputed tomography (µCT) and histological analysis to measure the regeneration of osseous and soft tissue in extraction sockets. Human umbilical vein endothelial cells (HUVECs) were isolated and cultured with endothelial cell medium (ECM). HUVECs were then divided into three groups: 1) Control: ECM; 2) Zol: ECM+Zol; 3) sEV-AT: ECM+Zol+sEV-AT. We evaluated the proliferation, tube formation and migration of HUVECs in each group.
Rats treated with Zol+Dex showed BRONJ-like lesions including open wounds, necrotic bones, empty osteocyte lacunae and reduced osteoclasts. sEV-AT administration reduced BRONJ-like lesions by promoting soft tissue healing. µCT results showed that bone volume in extraction sockets in the sEV-AT group was larger than the Zol+Dex group. Histological analysis showed less necrotic bones and empty osteocyte lacunae in the sEV-AT group compared to the Zol+Dex group. Histological analysis also showed more osteoclasts, collagen fibers and blood vessels in the sEV-AT group compared to the Zol+Dex group. Furthermore, sEV-AT enhanced the proliferation, migration and tube formation of HUVECs which were inhibited by Zol.
Our findings indicate that sEV-AT prevent BRONJ in rats. Angiogenesis promotion contributes to the prevention of BRONJ.
双膦酸盐相关颌骨坏死（BRONJ）尚无确切的治疗方法。脂肪组织来源的小细胞外囊泡（sEV-AT）已被证明在促进组织再生方面有效。本研究的目的是评估给予sEV-AT对大鼠BRONJ样病变的影响。
皮下注射唑来膦酸（Zol）和地塞米松（Dex）建立BRONJ大鼠模型。大鼠随机分为三组：1）对照组；2）Zol+Dex组；3）sEV-AT组。首次给药两周后拔除上颌左侧第一磨牙。在sEV-AT组，拔牙后每隔三天静脉注射sEV-AT。我们进行了咬合面图像、显微计算机断层扫描（µCT）和组织学分析，以测量拔牙窝内骨组织和软组织的再生情况。分离人脐静脉内皮细胞（HUVECs），并用内皮细胞培养基（ECM）进行培养。然后将HUVECs分为三组：1）对照组：ECM；2）Zol组：ECM+Zol；3）sEV-AT组：ECM+Zol+sEV-AT。我们评估了每组中HUVECs的增殖、管腔形成和迁移情况。
接受Zol+Dex治疗的大鼠出现了BRONJ样病变，包括开放性伤口、坏死骨、空的骨细胞陷窝和破骨细胞减少。给予sEV-AT通过促进软组织愈合减轻了BRONJ样病变。µCT结果显示，sEV-AT组拔牙窝内的骨体积大于Zol+Dex组。组织学分析表明，与Zol+Dex组相比，sEV-AT组的坏死骨和空的骨细胞陷窝更少。组织学分析还显示，与Zol+Dex组相比，sEV-AT组的破骨细胞、胶原纤维和血管更多。此外，sEV-AT增强了被Zol抑制的HUVECs的增殖、迁移和管腔形成。
我们的研究结果表明，sEV-AT可预防大鼠BRONJ。促进血管生成有助于预防BRONJ。
