Regulation Of Skeletal Growth

纵向骨生长发生在生长板，这是一层薄薄的软骨，位于长骨和椎骨的末端附近。生长板包含三个主要层：静息区、增殖区和肥厚区。我们已经证明，休息区含有干细胞样细胞，能够产生增殖软骨细胞的新克隆。我们还表明，休止区指导增殖克隆的空间方向，使它们形成与骨长轴平行的柱状结构。这些增殖细胞经历克隆扩增，随后细胞肥大。然后将肥厚的软骨重塑成骨组织。净效应是在生长板的底部逐渐产生新的骨组织，导致骨伸长。生长板软骨细胞增殖的速度，从而纵向骨生长的速度，随着年龄的增长而下降，并最终停止。我们有证据表明，这种软骨细胞增殖的下降是因为生长板干细胞样细胞具有有限的增殖能力，并逐渐耗尽。最终，生长板被骨取代，这一过程称为骨骺融合。我们也有证据表明，当生长板软骨细胞的增殖能力最终耗尽时，骨骺融合被触发。我们的研究结果进一步表明，雌激素加速生长板软骨细胞的增殖衰竭，导致线状生长早期终止，从而导致骺融合早期。与这一假设相一致，我们发现雌激素受体- α和- β在整个出生后发育过程中都在生长板软骨细胞中表达。

Longitudinal bone growth occurs at the growth plate, a thin layer of cartilage which lies near the ends of long bones and vertebrae. The growth plate contains three principal layers, the resting, proliferative, and hypertrophic zones. We have demonstrated that the resting zone contains stem-like cells that are capable of generating new clones of proliferative chondrocytes. We have also shown that the resting zone directs the spatial orientation of the proliferative clones, causing them to form columns parallel to the long axis of the bone. These proliferative cells undergo clonal expansion followed by cellular hypertrophy. The hypertrophic cartilage is then remodeled into bone tissue. The net effect is that new bone tissue is progressively created at the bottom of the growth plate, resulting in bone elongation. The rate of growth plate chondrocyte proliferation, and thus the rate of longitudinal bone growth, decreases with age and eventually stops. We have shown evidence that this decline in chondrocyte proliferation occurs because the growth plate stem-like cells have a finite proliferative capacity which is gradually exhausted. Eventually, the growth plate is replaced by bone, a process termed epiphyseal fusion. We have also shown evidence that epiphyseal fusion is triggered when the proliferative capacity of the growth plate chondrocytes is finally exhausted. Our findings further suggest that estrogen accelerates the proliferative exhaustion of the growth plate chondrocytes, causing early termination of linear growth and thus early epiphyseal fusion. Consistent with this hypothesis, we have found that estrogen receptors -alpha and -beta are both expressed in growth plate chondrocytes throughout postnatal development. The process of bone growth not only determines body size, but also partially determines the structural integrity of the skeleton. Thus, understanding skeletal growth may provide insight into the origins of osteoporosis. For example, it is often assumed that decreased bone mineral acquisition during childhood will cause a permanent decrease in bone mineral density which will increase the risk of fractures in late adulthood. To the contrary, we found evidence that bone mineral acquisition early in life has little or no effect on adult bone mass because many areas of the juvenile skeleton are replaced in toto through skeletal growth. This replacement of bone through skeletal growth can cause recovery even from severe osteoporosis in a growing animal. Thus, our data suggest that bone mineral acquisition in early life has little effect on adult bone density. If this concept generalizes to humans, then interventions to maximize peak bone mass would be more effective if directed at adolescents rather than young children.