PDF(Pubmed)
Abstract：
Research on the genetic mechanisms underlying human skeletal development and disease have largely relied on studies in mice. However, recently the zebrafish has emerged as a popular model for skeletal research. Despite anatomical differences such as a lack of long bones in their limbs and no hematopoietic bone marrow, both the cell types in cartilage and bone as well as the genetic pathways that regulate their development are remarkably conserved between teleost fish and humans. Here we review recent studies that highlight this conservation, focusing specifically on the cartilaginous growth zones (GZs) of endochondral bones. GZs can be unidirectional such as the growth plates (GPs) of long bones in tetrapod limbs or bidirectional, such as in the synchondroses of the mammalian skull base. In addition to endochondral growth, GZs play key roles in cartilage maturation and replacement by bone. Recent studies in zebrafish suggest key roles for cartilage polarity in GZ function, surprisingly early establishment of signaling systems that regulate cartilage during embryonic development, and important roles for cartilage proliferation rather than hypertrophy in bone size. Despite anatomical differences, there are now many zebrafish models for human skeletal disorders including mutations in genes that cause defects in cartilage associated with endochondral GZs. These point to conserved developmental mechanisms, some of which operate both in cranial GZs and limb GPs, as well as others that act earlier or in parallel to known GP regulators. Experimental advantages of zebrafish for genetic screens, high resolution live imaging and drug screens, set the stage for many novel insights into causes and potential therapies for human endochondral bone diseases.
摘要：
关于人类骨骼发育和疾病的遗传机制的研究在很大程度上依赖于小鼠的研究。然而,最近斑马鱼已成为骨骼研究的流行模型。尽管在解剖学上存在差异，例如四肢缺乏长骨，没有造血骨髓，软骨和骨骼中的细胞类型以及调节其发育的遗传途径在硬骨鱼和人类之间非常保守。在这里，我们回顾了最近强调这种保护的研究，特别关注软骨内骨的软骨生长区（GZs）。GZ可以是单向的，例如四足动物四肢长骨的生长板（GP）或双向的，例如在哺乳动物颅底的综合软骨中。除了软骨内生长，GZs在软骨成熟和骨置换中起关键作用。斑马鱼的最新研究表明软骨极性在GZ功能中的关键作用，令人惊讶的是，在胚胎发育过程中调节软骨的信号系统的早期建立，和软骨增殖的重要作用而不是骨大小的肥大。尽管解剖学上存在差异，现在有许多人类骨骼疾病的斑马鱼模型，包括导致与软骨内GZs相关的软骨缺陷的基因突变。这些指向保守的发育机制，其中一些在颅骨GZ和肢体GP中都有作用，以及其他与已知的GP监管者更早或并行行动的人。斑马鱼遗传筛选的实验优势，高分辨率实时成像和药物屏幕，为人类软骨内骨疾病的病因和潜在疗法提供了许多新颖的见解。
