Catch-up growth is associated with delayed senescence of the growth plate in rabbits.

In mammals, release from growth-inhibiting conditions results in catch-up growth. To explain this phenomenon, we proposed the following model: 1) The normal senescent decline in growth plate function depends not on age per se, but on the cumulative number of replications that growth plate chondrocytes have undergone. 2) Conditions that suppress growth plate chondrocyte proliferation therefore slow senescence. 3) After transient growth inhibition, growth plates are thus less senescent and hence show a greater growth rate than expected for age, resulting in catch-up growth. To test this model, we administered dexamethasone to growing rabbits to suppress linear growth. After stopping dexamethasone, catch-up growth occurred. In distal femoral growth plates of untreated controls, we observed a senescent decline in the growth rate and in the heights of the proliferative zone, hypertrophic zone, and total growth plate. During the period of catch-up growth, in the animals previously treated with dexamethasone, the senescent decline in all these variables was delayed. Prior treatment with dexamethasone also delayed epiphyseal fusion. These findings support our model that linear catch-up growth is caused, at least in part, by a delay in growth plate senescence.

Effects of estrogen on growth plate senescence and epiphyseal fusion.

Estrogen is critical for epiphyseal fusion in both young men and women. In this study, we explored the cellular mechanisms by which estrogen causes this phenomenon. Juvenile ovariectomized female rabbits received either 70 microg/kg estradiol cypionate or vehicle i.m. once a week. Growth plates from the proximal tibia, distal tibia, and distal femur were analyzed after 2, 4, 6, or 8 weeks of treatment. In vehicle-treated animals, there was a gradual senescent 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. Estrogen treatment accelerated the senescent decline in all of these parameters. 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 (i) epiphyseal fusion is triggered when the proliferative potential of growth plate chondrocytes is exhausted; and (ii) 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.

Regulation of growth plate chondrogenesis by bone morphogenetic protein-2.

Bone morphogenetic proteins (BMPs) regulate embryonic skeletal development. We hypothesized that BMP-2, which is expressed in the growth plate, also regulates growth plate chondrogenesis and longitudinal bone growth. To test this hypothesis, fetal rat metatarsal bones were cultured for 3 days in the presence of recombinant human BMP-2. The addition of BMP-2 caused a concentration-dependent acceleration of metatarsal longitudinal growth. As the rate of longitudinal bone growth depends primarily on the rate of growth plate chondrogenesis, we studied each of its three major components. BMP-2 stimulated chondrocyte proliferation in the epiphyseal zone of the growth plate, as assessed by [(3)H]thymidine incorporation. BMP-2 also caused an increase in chondrocyte hypertrophy, as assessed by quantitative histology and enzyme histochemistry. A stimulatory effect on cartilage matrix synthesis, assessed by (35)SO(4) incorporation into glycosaminoglycans, was produced only by the highest concentration of BMP-2. These BMP-2-mediated stimulatory effects were reversed by recombinant human Noggin, a glycoprotein that blocks BMP-2 action. In the absence of exogenous BMP-2, Noggin inhibited metatarsal longitudinal growth, chondrocyte proliferation, and chondrocyte hypertrophy, which suggests that endogenous BMPs stimulate longitudinal bone growth and chondrogenesis. We conclude that BMP-2 accelerates longitudinal bone growth by stimulating growth plate chondrocyte proliferation and chondrocyte hypertrophy.