Catch-Up Growth Is Associated with Delayed Senescence of the Growth Plate in Rabbits

Abstract

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. More than 35 y ago, Prader, Tanner, and von Harnack observed that children undergo supranormal linear growth after release from growth-inhibiting conditions (1). This phenomenon, termed catch-up growth, was attributed to a CNS mechanism that compares the individual's actual body size with an age-appropriate set-point and then adjusts the growth rate accordingly (2). However, this neuroendocrine hypothesis has not been subjected to a definitive experimental test.More recently, we demonstrated that transient growth inhibition within a single growth plate is followed by local catch-up growth (3). This local catch-up growth cannot be readily explained by a systemic mechanism, which would have affected all the growth plates equally. Instead, it suggests that catch-up growth is due, at least in part, to a mechanism intrinsic to the growth plate.To account for this finding, we speculated that catch-up growth might be caused by a delay in the process of growth plate senescence. The growth plate, a layer of cartilage located between the epiphysis and the metaphysis of mammalian long bones, is composed of three distinct zones: the resting zone, proliferative zone, and hypertrophic zone. With increasing age, the growth plate undergoes a program of structural and functional changes. These senescent changes include a progressive decline in the growth rate accompanied by a decrease in the heights of the proliferative zone (4), the hypertrophic zone (5), and the overall growth plate (6). In some mammals, including humans and rabbits, the senescent growth plates are eventually replaced by bone tissue, a process termed epiphyseal fusion.Specifically, to explain the mechanism underlying local catch-up growth, we hypothesized that growth plate senescence is not a function of age per s...

Catch-up growth after dexamethasone withdrawal occurs in cultured postnatal rat metatarsal bones

“…Accordingly, normalization of cell proliferation in 19 days Dexa-exposed bones was not observed 5 days after cessation of treatment in contrast to bones exposed only for 7 days. Our ex vivo data are in line with the previously published in vivo observation that growth plate chondrocyte proliferation rate is increased upon cessation of systemic glucocorticoid treatment (Gafni et al 2001), previous tamoxifen treatment ( Karimian et al 2008) and hypothyroidism (Marino et al 2008). To our knowledge, it has previously not been demonstrated that elevated proliferation during catch-up growth is attributed to local mechanisms within the growth plate.…”

Growth retardation induced by dexamethasone is associated with increased apoptosis of the growth plate chondrocytes

“…Apoptotic resting/early proliferative chondrocytes were rare in occasional sections from control animals but after dexamethasone treatment an 18-fold increase was observed. It has been suggested that the observed catch-up growth after dexamethasone treatment is due to delayed senescence of the growth plate as the chondrocytes have undergone fewer replications due to the inhibitory effect of dexamethasone on cell proliferation (Gafni et al 2001). In every dynamic model of growth there are two parameters for optimal growth: cell proliferation and cell death.…”

Effects of glucocorticoids on growth and bone mineralization

“…A suspensão do tratamento com GC é seguida por um crescimento compensatório 40 , causado, pelo menos em parte, por um mecanismo intrínseco da placa de crescimento 41 Um dos efeitos principais dos GC no osso é diminuir a taxa de formação óssea; esse efeito é reversível, segundo dados obtidos em pacientes após cura de síndrome de Cushing em acompanhamento de longo prazo, através de exames seriados de densitometria por emissão dupla de raio X (DXA) 43 . Essa recuperação ocorre devido à preservação da arquitetura trabecular, mantendo-se, assim, intacto o vigamento no qual os osteoblastos podem sintetizar osso novo, após a suspensão dos GC.…”