Regulation Of Skeletal Growth

在哺乳动物中，长骨的生长发生在生长板上，生长板是一种软骨结构，包括三个主要层，静止区、增殖区和肥大区。休息区的功能还没有被很好地理解。我们手术切除了兔尺骨远端生长板上的增殖区和肥大区，只留下了休息区。在一周内，一个完整的增殖带和肥大带通常会再生。接下来，我们通过手术操作生长板，将静止区软骨异位放置在增殖柱旁边。异位静止区软骨诱导邻近增殖区软骨细胞方向90度移位，抑制其肥大分化。我们的发现表明，静止区软骨在生长板软骨内的骨形成中至少起着三个重要的作用：(1)它含有干细胞样细胞，可以产生增殖软骨细胞的克隆；(2)它产生生长板定向因子，它是一种形态原，引导增殖克隆排列成平行于骨长轴的柱状；(3)它产生一种形态原，抑制附近增殖区软骨细胞的终末分化，从而负责将生长板组织成不同的增殖区和肥大区。随着年龄的增长，哺乳动物的生长板经历了结构和功能的衰老变化，导致线性增长率下降。在包括人类在内的一些哺乳动物中，生长板最终在性成熟时被骨骼取代。这一过程被称为骨骺融合，严重依赖于雌激素。雌激素导致骨骺闭合的机制尚不清楚。利用体内模型，我们发现雌激素加速了正常衰老的生长板结构和功能的下降，包括胫骨生长率、软骨细胞增殖率、生长板高度、增殖软骨细胞数、肥大软骨细胞数、终末肥大软骨细胞大小和柱状密度的下降。在衰老的生长板中，骨痂融合是一个突然的事件，所有剩余的软骨细胞都被骨元素迅速取代。当软骨细胞增殖率接近零时发生融合。雌激素导致这种增殖性衰竭和融合发生得更早。我们的数据表明：1)当生长板软骨细胞的增殖潜能耗尽时，骨骺融合被触发；2)雌激素不直接诱导生长板成骨；相反，雌激素加速生长板的程序性衰老，从而导致更早的增殖衰竭，从而更早的融合。我们还在进行阿仑磷酸钠治疗青少年特发性骨质疏松症的随机试验。在这项研究的一个分支中，我们评估了可能纳入试验的转介患者的诊断准确性。我们发现，大多数被诊断为骨质疏松症的儿童，实际上都有正常的骨密度。这种令人震惊的过度诊断率是由于对双能X射线吸收扫描(DEXA)扫描的错误解释。最常见的错误是使用T-Score(与年轻人相比的标准差分数)来诊断尚未达到骨量峰值的儿童的骨质疏松症。这种过度诊断可能会引发不必要的额外检查，孩子和父母的焦虑，体力活动的限制，以及医疗干预。我们还将完成一项针对非生长激素缺乏性极矮儿童的生长激素治疗的随机、双盲、安慰剂对照试验。这项研究的数据分析表明，与之前基于非随机试验的报告相反，生长激素治疗不会改变青春期的时间或速度。

In mammals, growth of long bones occurs at the growth plate, a cartilage structure that contains three principal layers, the resting, proliferative, and hypertrophic zones. The function of the resting zone is not well understood. We surgically removed the proliferative and hypertrophic zones from the rabbit distal ulnar growth plate, leaving only the resting zone. Within one week, a complete proliferative and hypertrophic zone often regenerated. Next, we surgically manipulated growth plates to place resting zone cartilage ectopically alongside the proliferative columns. Ectopic resting zone cartilage induced a 90-degree shift in the orientation of nearby proliferative zone chondrocytes and inhibited their hypertrophic differentiation. Our findings suggest that resting zone cartilage serves at least three important roles in endochondral bone formation at the growth plate: (1) it contains stem-like cells that give rise to clones of proliferative chondrocytes, (2) it produces a growth plate-orienting factor, a morphogen that directs the alignment of the proliferative clones into columns parallel to the long axis of the bone, and (3) it produces a morphogen that inhibits terminal differentiation of nearby proliferative zone chondrocytes and thus is responsible for the organization of the growth plate into distinct zones of proliferation and hypertrophy. With age, the mammalian growth plate undergoes structural and functional senescent changes which cause a decrease in linear growth rate. In some mammals, including humans, the growth plates are eventually replaced by bone at the time of sexual maturation. This process, termed epiphyseal fusion, depends critically on estrogen. The mechanism by which estrogen causes epiphyseal closure is not known. Using an in vivo model, we found that estrogen accelerated the normal senescent decline in growth plate structure and function, including the decline in tibial growth rate, rate of chondrocyte proliferation, growth plate height, number of proliferative chondrocytes, number of hypertrophic chondrocytes, size of terminal hypertrophic chondrocytes, and column density. In senescent growth plates, epiphyseal fusion was observed to be an abrupt event in which all remaining chondrocytes were rapidly replaced by bone elements. Fusion occurred when the rate of chondrocyte proliferation approached zero. Estrogen caused this proliferative exhaustion and fusion to occur earlier. Our data suggest that 1) Epiphyseal fusion is triggered when the proliferative potential of growth plate chondrocytes is exhausted; 2) Estrogen does not induce growth plate ossification directly; instead, estrogen accelerates the programmed senescence of the growth plate, thus causing earlier proliferative exhaustion and consequently earlier fusion. We are also conducting a randomized trial of alendronate for the treatment of idiopathic juvenile osteoporosis. In an offshoot of this study, we assessed the accuracy of diagnosis in patients referred for possible inclusion in the trial. We found that the majority of children referred with a diagnosis of osteoporosis, in fact, have a normal bone mineral density. This alarming rate of overdiagnosis was due to errors in the interpretation of the dual-energy x-ray absorptiometry (DEXA) scan. The most frequent error was the use of T-score (standard deviation score compared to young adults) to diagnose osteoporosis in children who had not yet achieved peak bone mass. This overdiagnosis can precipitate unnecessary additional testing, anxiety on the part of the child and parents, restriction of physical activity, and medical intervention. We are also completing a randomized double-blind placebo-controlled trial of growth hormone therapy in children with non-growth hormone-deficient extreme short stature. Analysis of data from this study indicate that, contrary to previous reports based on nonrandomized trials, growth hormone therapy does not alter the timing or pace of puberty.