Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, 138673, Singapore.
Department of Biomedical Science, Firth Court, Western Bank, The University of Sheffield, Sheffield, S10 2TN, United Kingdom.
Dis Model Mech. 2019 Sep 3;12(9):dmm037630. doi: 10.1242/dmm.037630.
Reduced bone quality or mineral density predict susceptibility to fracture and also attenuate subsequent repair. Bone regrowth is also compromised by bacterial infection, which exacerbates fracture site inflammation. Because of the cellular complexity of fracture repair, as well as genetic and environmental influences, there is a need for models that permit visualisation of the fracture repair process under clinically relevant conditions. To characterise the process of fracture repair in zebrafish, we employed a crush fracture of fin rays, coupled with histological and transgenic labelling of cellular responses; the results demonstrate a strong similarity to the phased response in humans. We applied our analysis to a zebrafish model of osteogenesis imperfecta (OI), which shows reduced bone quality, spontaneous fractures and propensity for non-unions. We found deficiencies in the formation of a bone callus during fracture repair in our OI model and showed that clinically employed antiresorptive bisphosphonates can reduce spontaneous fractures in OI fish and also measurably reduce fracture callus remodelling in wild-type fish. The mutant, which has reduced osteoclast numbers, also showed reduced callus remodelling. Exposure to excessive bisphosphonate, however, disrupted callus repair. Intriguingly, neutrophils initially colonised the fracture site, but were later completely excluded. However, when fractures were infected with , neutrophils were retained and compromised repair. This work elevates the zebrafish bone fracture model and indicates its utility in assessing conditions of relevance to an orthopaedic setting with medium throughput.This article has an associated First Person interview with the first author of the paper.
骨质量或矿物质密度降低可预测骨折易感性，并减弱随后的修复。细菌感染也会损害骨再生，加剧骨折部位炎症。由于骨折修复的细胞复杂性，以及遗传和环境的影响，需要建立模型，以便在临床相关条件下观察骨折修复过程。为了描述斑马鱼骨折修复过程，我们采用鳍射线压碎骨折，并结合细胞反应的组织学和转基因标记；结果表明与人类的分相反应具有很强的相似性。我们将我们的分析应用于成骨不全症（OI）的斑马鱼模型，该模型显示出骨质量降低、自发性骨折和非愈合倾向。我们发现我们的 OI 模型在骨折修复过程中骨痂形成存在缺陷，并表明临床上使用的抗吸收双膦酸盐可减少 OI 鱼的自发性骨折，并可显著减少野生型鱼的骨折痂重塑。破骨细胞数量减少的突变体也显示出骨痂重塑减少。然而，暴露于过多的双膦酸盐会破坏骨痂修复。有趣的是，中性粒细胞最初定植于骨折部位，但后来被完全排斥。然而，当骨折感染时，中性粒细胞被保留并损害修复。这项工作提升了斑马鱼骨折模型，并表明其在评估与矫形环境相关的条件方面具有中等通量的实用性。本文附有该论文第一作者的第一人称采访。
