Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions

摘要

The wide diversity of skeletal proportions in mammals is evident upon a survey of any natural history museum's collections and allows us to distinguish between species even when reduced to their calcified components. Similarly, each individual is comprised of a variety of bones of differing lengths. The largest contribution to the lengthening of a skeletal element, and to the differential elongation of elements, comes from a dramatic increase in the volume of hyper-trophic chondrocytes in the growth plate as they undergo terminal differentiation1"7. However, the mechanisms of chondrocyte volume enlargement have remained a mystery8"11. Here we use quantitative phase microscopy12 to show that mammalian chondrocytes undergo three distinct phases of volume increase, including a phase of massive cell swelling in which the cellular dry mass is significantly diluted. In light of the tight fluid regulatory mechanisms known to control volume in many cell types13, this is a remarkable mechanism for increasing cell size and regulating growth rate. It is, however, the duration of the final phase of volume enlargement by proportional dry mass increase at low density that varies most between rapidly and slowly elongating growth plates. Moreover, we find that this third phase is locally regulated through a mechanism dependent on insulin-like growth factor. This study provides a framework for understanding how skeletal size is regulated and for exploring how cells sense, modify and establish a volume set point.%在哺乳动物中，物种之间以及一个个体内的骨rn长度差异很大。每根长骨都是从胚胎中一个大rn小相似的软骨原基形成的。大小差别是日后通rn过对生长面(在一根长骨每端的“干骨后端”中rn所发现的一个软骨面)上的软骨细胞的生长的rn差异化调控形成的。Clifford Tabin及其同事利rn用“衍射相显微镜”来研究控制啮齿类动物差rn异化的骨生长的机制，发现生长面上的软骨细rn胞经历三个不同阶段的体积增加。正是在第三rn阶段，即细胞发生巨大膨胀的阶段(在该阶段rn中，细胞干物质被显著稀释)，快速伸长和慢rn速伸长的生长面之间的差异开始出现，骨长度rn之间的差别得以形成。