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^G242D;fms^j4e1 double-deficient zebrafish, which exhibited a greater deficiency of functional osteoclasts and displayed more severe osteopetrotic symptoms than the pu.1^G242D or 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.

破骨细胞是骨髓来源的骨吸收细胞。破骨细胞缺陷可导致骨质疏松症，这是一种以骨硬化为特征的遗传性疾病，目前尚无有效的药物治疗方法。众所周知，Pu.1和Fms是骨髓生成过程中的关键调节剂，它们在小鼠中的缺陷会导致破骨细胞数量减少，从而导致骨质疏松。然而，尚不清楚Pu.1和Fms在破骨细胞的发育中如何发生遗传相互作用以及骨石化的发病机理。在这里，我们对pu.1 ^{G242D进行了表征}；fms ^j4e1双缺陷斑马鱼，与pu.1 ^G242D或fms相比，表现出更大的功能性破骨细胞缺乏症并表现出更严重的骨质疏松症状^j4e1单突变体，表明Pu.1和Fms在破骨细胞发育调控中具有协同作用。我们进一步证明，Pu.1在破骨细胞形成中起主要作用，而Fms在破骨细胞成熟中起主要作用。重要的是，通过增加功能性破骨细胞的数量，在这些模型中用视黄酸进行药物治疗可显着缓解不同程度的骨质疏松症症状。因此，我们报告了骨科学的有价值的动物模型的发展，我们的结果为抗骨科学疗法的药物开发提供了启示。