尿囊素促进破骨细胞缺陷斑马鱼骨折修复
收稿日期: 2023-01-18
修回日期: 2023-02-27
网络出版日期: 2023-03-22
基金资助
国家重点研发计划(2018YFA0801000);国家自然科学基金项目(81770167)
The role of the allantoin in promoting fracture healing in osteoclast-deficient zebrafish
Received date: 2023-01-18
Revised date: 2023-02-27
Online published: 2023-03-22
Supported by
National Key Research and Development Program of China(2018YFA0801000);National Natural Science Foundation of China(81770167)
骨折愈合是一个由多细胞介导的多步骤的严密有序的过程，其中破骨细胞介导的骨重塑在骨折愈合中具有关键作用，其生成减少或者功能障碍不仅导致骨折的易发生，还会引起骨折愈合障碍。但是，目前关于破骨细胞缺陷所致的骨折愈合障碍的研究较少，并且临床上尚缺乏针对破骨细胞缺陷所致骨折愈合障碍的治疗药物。斑马鱼(Danio rerio)骨骼系统中的细胞类型和调节途径与哺乳动物高度相似，使得其被广泛地运用于骨骼相关的研究。为了研究破骨细胞缺陷所致的骨折愈合障碍过程以及寻找有潜力的治疗药物，本研究使用前期建立的fms基因突变斑马鱼(fmsj4e1)构建了体内破骨细胞缺陷骨折模型，结果发现功能性破骨细胞减少可在骨折早期影响骨折的愈合；使用离体鳞片培养系统用于筛选破骨细胞靶向药物，获得了可以激活破骨细胞的小分子化合物尿囊素(allantoin，ALL)；随后，在体内fmsj4e1骨折缺陷模型中验证了ALL对破骨细胞的激活作用以及对骨折修复的促进作用；最后，通过对破骨细胞生成和成熟过程的分析，发现ALL可能通过调节RANKL/OPG来促进破骨细胞的成熟，从而促进fmsj4e1骨折愈合。本研究为未来改善破骨细胞缺陷引起的骨折愈合障碍提供了潜在的新方法。
关键词： 斑马鱼fmsj4e1突变体; 破骨细胞; 药物筛选; 尿囊素; 骨折愈合
李凯伦, 卢荆奥, 陈小辉, 张文清, 刘伟 . 尿囊素促进破骨细胞缺陷斑马鱼骨折修复[J]. 遗传, 2023 , 45(4) : 341 -353 . DOI: 10.16288/j.yczz.23-015
Fracture healing is a rigorous and orderly process with multiple steps that are mediated by multiple cells. During this process, osteoclast-mediated bone remodeling plays a critical role, and its abnormal activity leads not only to fracture susceptibility but also to impaired fracture healing. However, few studies have focused on impaired healing caused by osteoclast defects, and clinical drugs for this type of impaired fracture healing are still lacking. The cell types and regulatory pathways in the zebrafish skeletal system are highly similar to those of mammals, making the zebrafish skeletal system being widely used for skeletal-related studies. To study the process of fracture healing disorders caused by osteoclast defects and discover potential therapeutic drugs, we established an in vivo osteoclast-deficient fracture model using a previously generated fms gene mutant zebrafish (fmsj4e1). The results showed that reduced functional osteoclasts could affect fracture repair in the early stages of fracture. Then we applied an in vitro scale culture system to screen for osteoclast-activating drugs. We found the small molecule compound allantoin (ALL) being able to activate osteoclasts. Subsequently, we verified the activation role of ALL on osteoclasts and the promotion of fracture repair in an in vivo fmsj4e1 fracture defect model. Finally, by examining the osteoclastogenesis and maturation process, we found that ALL may promote osteoclast maturation by regulating RANKL/OPG, thus promoting fmsj4e1 fracture healing. Our study provides a potential new approach for the future improvement of fracture healing disorders caused by osteoclast defects.
Key words： zebrafish fmsj4e1 mutant; osteoclasts; drug screening; allantoin; fracture healing
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