Program in Developmental Endocrinology and Genetics (O.N., M.W., E.B.M.L., J.L.M., K.M.B., J.B.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Center for Molecular Medicine and Pediatric Endocrinology Unit (O.N., E.B.M.L.), Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Endocrinology. 2014 Aug;155(8):2892-9. doi: 10.1210/en.2013-2175. Epub 2014 Apr 7.
With age, growth plate cartilage undergoes programmed senescence, eventually causing cessation of bone elongation and epiphyseal fusion. Estrogen accelerates this developmental process. We hypothesized that senescence occurs because progenitor cells in the resting zone are depleted in number and that estrogen acts by accelerating this depletion. To test this hypothesis, juvenile ovariectomized rabbits received injections of estradiol cypionate or vehicle for 5 weeks, and then were left untreated for an additional 5 weeks. Exposure to estrogen accelerated the normal decline in growth plate height and in the number of proliferative and hypertrophic chondrocytes. Five weeks after discontinuation of estrogen treatment, these structural parameters remained advanced, indicating an irreversible advancement in structural senescence. Similarly, transient estrogen exposure hastened epiphyseal fusion. Estrogen also caused a more rapid decline in functional parameters of growth plate senescence, including growth rate, proliferation rate, and hypertrophic cell size. However, in contrast to the structural parameters, once the estrogen treatment was discontinued, the growth rate, chondrocyte proliferation rate, and hypertrophic cell size all normalized, suggesting that estrogen has a reversible, suppressive effect on growth plate function. In addition, estrogen accelerated the normal loss of resting zone chondrocytes with age. This decrease in resting zone cell number did not appear to be due to apoptosis. However, it was maintained after the estrogen treatment stopped, suggesting that it represents irreversible depletion. The findings are consistent with the hypothesis that estrogen causes irreversible depletion of progenitor cells in the resting zone, thus irreversibly accelerating structural senescence and hastening epiphyseal fusion. In addition, estrogen reversibly suppresses growth plate function.
随着年龄的增长，生长板软骨经历程序性衰老，最终导致骨伸长和骺融合停止。雌激素加速了这一发育过程。我们假设衰老的发生是由于静止区的祖细胞数量减少，而雌激素通过加速这种耗竭起作用。为了验证这一假设，幼年去卵巢兔接受雌二醇环戊丙酸酯或载体注射 5 周，然后再未治疗 5 周。暴露于雌激素加速了生长板高度和增殖和肥大软骨细胞数量的正常下降。停止雌激素治疗 5 周后，这些结构参数仍然先进，表明结构衰老的不可逆转进展。同样，短暂的雌激素暴露加速了骺融合。雌激素还导致生长板衰老的功能参数更快下降，包括生长速度、增殖率和肥大细胞大小。然而，与结构参数不同，一旦停止雌激素治疗，生长速度、软骨细胞增殖率和肥大细胞大小均恢复正常，表明雌激素对生长板功能具有可逆的抑制作用。此外，雌激素加速了静止区软骨细胞随年龄的正常丧失。静止区细胞数量的减少似乎不是由于细胞凋亡。然而，它在雌激素治疗停止后仍然存在，这表明它代表了不可逆转的耗竭。这些发现与雌激素导致静止区祖细胞不可逆转耗竭的假设一致，从而不可逆转地加速结构衰老并加速骺融合。此外，雌激素可逆地抑制生长板功能。
