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。在生长板处，软骨内骨化导致新骨小梁的形成。然而，纵向骨生长不仅需要形成松质骨（在长骨内部发现的松质骨），而且需要形成皮质骨（在长骨外围发现的致密骨）。负责骨皮质纵向生长的机制以前尚未确定。我们现在已经证明，皮质的纵向生长是通过生长板周围形成的骨小梁的合并而发生的。在靠近骨膜的骨小梁合并区域，与远离骨膜的骨小梁相比，成骨细胞表面（骨表面被成骨细胞覆盖的部分）增加。破骨细胞表面无差异。在体外，成骨细胞增殖增加时，骨膜或骨膜条件培养基的存在下培养。在骨膜和松质骨之间插入可渗透或不可渗透的膜并不能阻止皮质形成。基于这些研究，我们得出结论，干骺端皮质骨是由软骨内松质骨合并形成的。这种聚结与周围骨小梁中成骨细胞表面的增加有关。成骨细胞表面的增加可能是由于骨膜的诱导作用;骨膜在体外刺激成骨细胞增殖，但在体内干骺端皮质骨形成不需要。 我们已经发现了纵向骨生长随年龄增长而减慢的证据，因为生长板软骨细胞具有逐渐耗尽的有限增殖能力。雌激素加速了这一过程，导致线性生长提前终止和骨骺早期融合。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。我们最近完成了一项对性早熟女孩的临床研究。在这些女孩中，性早熟导致生长板暴露在高水平的雌激素中。我们发现临床证据表明，这些女孩的生长板软骨细胞的增殖性软骨化加速，加速的严重程度与雌激素暴露的严重程度相关。这些发现与我们的假设一致，即雌激素加速人生长板软骨细胞的增殖耗竭。

Longitudinal bone growth occurs at the growth plate, a thin layer of cartilage which lies near the ends of long bones and vertebrae. At the growth plate, endochondral ossification results in the formation of new trabecular bone. However, longitudinal bone growth requires the formation not only of trabecular bone (spongy bone found in the interior of long bones) but also cortical bone (dense bone found at the periphery of long bones). The mechanisms responsible for longitudinal growth of the bone cortex have not previously been identified. We have now demonstrated that longitudinal growth of the cortex occurs by coalescence of trabecular bone formed at the periphery of the growth plate. In this region of coalescing trabeculae close to the periosteum, osteoblast surface (the fraction of bone surface covered by osteoblasts) was increased compared to trabeculae farther from the periosteum. Osteoclast surface did not differ. In vitro, osteoblast proliferation was increased when cultured in the presence of periosteum or periosteum-conditioned medium. Insertion of permeable or impermeable membranes between periosteum and spongiosa did not prevent cortex formation. Based on these studies we conclude that metaphyseal cortical bone is formed by coalescence of endochondral trabecular bone. This coalescence is associated with increased osteoblast surface in the peripheral trabecular bone. The increased osteoblast surface could be due to inductive effects of periosteum; periosteum stimulates osteoblast proliferation in vitro, but is not required for metaphyseal cortical bone formation in vivo. We have found evidence that longitudinal bone growth slows with age because the growth plate chondrocytes have a finite proliferative capacity that is gradually exhausted. Estrogen accelerates this process, causing early termination of linear growth and 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. We have recently completed a clinical study of girls with precocious puberty. In these girls, the precocious puberty caused the growth plates to be exposed to high levels of estrogen. We found clinical evidence that proliferative exhausion of the growth plate chondrocytes in these girls had been accelerated and that the severity of the acceleration correlated with the severity of the estrogen exposure. These findings are consistent with our hypothesis that estrogen accelerates proliferative exhaustion in human growth plate chondrocytes.