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.
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