Differential ageing of growth plate cartilage determines skeletal proportions

Bones at different anatomical locations vary dramatically in size. The mechanisms responsible for these size differences are poorly understood. Bone elongation occurs at the growth plates and advances rapidly in early life but then progressively slows due to a developmental program termed growth plate senescence. This developmental program includes declines in cell proliferation and hypertrophy, depletion of cells in all growth plate zones, and extensive underlying changes in the expression of growth-regulating genes. Here we use RNA-Seq to compare changes of gene expression with age in the longer bone (tibia, 1- vs 4-wk) with the difference of gene expression between long and short bones (tibia vs phalanx) at 1wk. We found that the developmental program of growth plate senescence is more advanced in the shorter bone and this differential senescence (or aging) underlies the disparities in bone length.不同解剖部位的骨骼尺寸差异悬殊，而导致这类尺寸差异的分子机制目前仍不甚明晰。骨骼的延长发生于生长板（growth plate）中，在生命早期进展迅速，随后因被称为生长板衰老（growth plate senescence）的发育程序而逐渐放缓。该发育程序包含细胞增殖与肥大能力的下降、所有生长板区域细胞的耗竭，以及生长调控基因表达层面的广泛改变。本研究采用RNA测序（RNA-Seq）技术，对比了较长骨骼（胫骨（tibia），1周龄与4周龄样本）随年龄增长的基因表达变化，以及1周龄时长骨骼与短骨骼（胫骨与指骨（phalanx））间的基因表达差异。我们发现，短骨中的生长板衰老发育程序进展更为超前，这种差异性衰老（或老化）正是骨骼长度差异的成因。