Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions
Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions
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DOI：
10.1371/journal.pbio.2005263
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发表时间：
2018-07-01
期刊：
影响因子：
9.8
通讯作者：
Baron, Jeffrey
中科院分区：
文献类型：
--
作者：
Lui, Julian C.;Jee, Youn Hee;Baron, Jeffrey
不同解剖位置的骨骼大小差异很大。例如，人类的股骨比手指和脚趾的趾骨长20倍。造成这些尺寸差异的机制知之甚少。骨伸长发生在生长板处，并在生命早期迅速发展，但随后由于称为生长板衰老的发育程序而逐渐减慢。“这种发育程序包括细胞增殖和肥大的下降，所有生长板区域的细胞耗竭，以及生长调节基因表达的广泛潜在变化。在这里，我们显示的证据表明，这些功能，结构和分子衰老的变化发生在较小的骨骼（掌骨，趾骨）的生长板早于较大的骨骼（股骨，胫骨）的生长板，这种差异老化有助于骨长度的差异。我们还证明了不同骨骼之间差异老化的分子机制涉及关键旁分泌调节途径的调节，包括胰岛素样生长因子（Igf），骨形态发生蛋白（Bmp）和Wingless和Int-1（Wnt）信号传导。总之，研究结果表明，不同骨骼长度的显着差异，这是正常哺乳动物骨骼比例的特征，部分是通过调节生长板衰老的进展来实现的。
Bones at different anatomical locations vary dramatically in size. For example, human femurs are 20-fold longer than the phalanges in the fingers and toes. 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 show evidence that these functional, structural, and molecular senescent changes occur earlier in the growth plates of smaller bones (metacarpals, phalanges) than in the growth plates of larger bones (femurs, tibias) and that this differential aging contributes to the disparities in bone length. We also show evidence that the molecular mechanisms that underlie the differential aging between different bones involve modulation of critical paracrine regulatory pathways, including insulin-like growth factor (Igf), bone morphogenetic protein (Bmp), and Wingless and Int-1 (Wnt) signaling. Taken together, the findings reveal that the striking disparities in the lengths of different bones, which characterize normal mammalian skeletal proportions, is achieved in part by modulating the progression of growth plate senescence.