Regulation Of Skeletal Growth

纵向骨生长发生在生长板，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，静止区、增殖区和肥大区。我们已经证明，休息区含有干细胞样细胞，能够产生新的克隆增殖软骨细胞。我们还表明，静止区指导增殖克隆的空间方向，使它们形成平行于骨长轴的柱状物。这些增殖细胞经历克隆扩增，随后是细胞肥大。然后，肥大的软骨被重塑成骨组织。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率，以及因此纵向骨生长的速率，随着年龄的增长而降低并最终停止。我们已经证明，软骨细胞增殖的这种下降是因为生长板干细胞样细胞具有有限的增殖能力，这种增殖能力逐渐耗尽。最终，生长板被骨所取代，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耗竭，导致早期终止线性生长，从而早期骨骺融合。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。 骨骼生长的过程不仅决定了身体的大小，而且部分决定了骨骼的结构完整性。因此，了解骨骼的生长可能会提供深入了解骨质疏松症的起源。例如，人们通常认为，儿童时期骨矿物质获取减少将导致骨矿物质密度永久性降低，这将增加成年后期骨折的风险。相反，我们发现的证据表明，在生命早期骨矿物质的获取对成年骨量几乎没有影响，因为青少年骨骼的许多领域通过骨骼生长完全取代。这种通过骨骼生长的骨替代甚至可以使生长中的动物从严重的骨质疏松症中恢复。因此，我们的数据表明，早期骨矿物质的获得对成年骨密度的影响很小。如果这一概念推广到人类，那么针对青少年而不是幼儿的干预措施将更有效，以最大限度地提高峰值骨量。

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.