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.
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