The synergistic role of Pu.1 and Fms in zebrafish osteoclast-reducing osteopetrosis and possible therapeutic strategies  

作　　者：Wei Liu Qianqian Di Kailun Li Jing Li Ning Ma Zhibin Huang Jiahao Chen Sheng Zhang Wenqing Zhang Yiyue Zhang 

机构地区：[1]Division of Cell,Developmental and Integrative Biology,School of Medicine,South China University of Technology,Guangzhou,510006,China [2]Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes,Department of Developmental Biology,School of Basic Medical Sciences,Southern Medical University,Guangzhou,510515,China [3]Department of Orthopedics and Traumatology,Nanfang Hospital,Southern Medical University,Guangzhou,510515,China

出　　处：《Journal of Genetics and Genomics》2020年第9期535-546,共12页遗传学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(31671525,81770167,31922023);the National key R&D program of China(2018YFA0800200,2018YFA0801000);the Fundamental Research Funds for the Central Universities(2019ZD54);GDUPS(2019)。

摘　　要：Osteoclasts are bone resorption cells of myeloid origin. Osteoclast defects can lead to osteopetrosis, a genetic disorder characterized by bone sclerosis for which there is no effective drug treatment. It is known that Pu.1 and Fms are key regulators in myelopoiesis, and their defects in mice can lead to reduced osteoclast numbers and consequent osteopetrosis. Yet how Pu.1 and Fms genetically interact in the development of osteoclasts and the pathogenesis of osteopetrosis is still unclear. Here, we characterized pu.1^(G242) D;fms^(j4e1) double-deficient zebrafish, which exhibited a greater deficiency of functional osteoclasts and displayed more severe osteopetrotic symptoms than the pu.1^(G242) Dor fms^(j4e1) single mutants, suggesting a synergistic function of Pu.1 and Fms in the regulation of osteoclast development. We further demonstrated that Pu.1 plays a dominant role in osteoclastogenesis, whereas Fms plays a dominant role in osteoclast maturation. Importantly, treatment with the drug retinoic acid significantly relieved the different degrees of osteopetrosis symptoms in these models by increasing the number of functional osteoclasts. Thus, we report the development of valuable animal models of osteopetrosis, and our results shed light on drug development for antiosteopetrosis therapy.

关 键 词：ZEBRAFISH Bone development OSTEOCLASTS OSTEOPETROSIS THERAPEUTICS 

分 类 号：R68[医药卫生—骨科学]