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PubMed2002

Parathyroid hormone receptor type 1/Indian hedgehog expression is preserved in the growth plate of human fetuses affected with fibroblast growth factor receptor type 3 activating mutations.

The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans, FGFR3 signaling does not down-regulate the main players of the IHH/PTHR1 pathway. Furthermore, we show that cells within the bone-perichondrial ring in controls and patients express IHH, PTHR1, and type 10 and type 1 collagen transcripts, suggesting that bone-perichondrial ring formation involves cells of both chondrocytic and osteoblastic phenotypes.

Achondroplasia↗
PubMed2002

Estrogen receptor-alpha and -beta are expressed throughout postnatal development in the rat and rabbit growth plate.

Estrogen regulates skeletal growth and promotes epiphyseal fusion. To explore the mechanisms underlying these effects we investigated the expression of estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in rat and rabbit growth plates during postnatal development, using immunohistochemistry. Immunoreactivity for ERalpha and ERbeta was observed in resting zone and proliferative zone chondrocytes at all ages studied for both rat (7, 14, 28 and 70 days of age) and rabbit (1, 7, 28 and 120 days of age). In the rat distal humerus and the rabbit proximal tibia, expression of both receptors in the hypertrophic zone was minimal at early ages, increasing only at the last time point prior to epiphyseal fusion. Expression was rarely seen in the hypertrophic zone of the rat proximal tibia, a growth plate that does not fuse until late in life. Therefore, we conclude that ERalpha and ERbeta are both expressed in the mammalian growth plate. The temporal and anatomical pattern suggests that ER expression in the hypertrophic zone in particular may play a role in epiphyseal fusion.

Aging↗
PubMed1989

Effect of somatomedin-C/insulin-like growth factor I and growth hormone on cultured growth plate and articular chondrocytes.

To determine whether growth hormone has a direct effect on skeletal tissues not mediated by somatomedins, and to better define the role of somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) in skeletal development, bovine growth plate, and rabbit articular and growth plate chondrocytes in primary culture were evaluated under a variety of experimental conditions designed to elicit growth hormone and Sm-C/IGF-I stimulation. Under none of these conditions did bovine growth plate chondrocytes respond to either homologous bovine growth hormone or heterologous hGH. Under the same conditions, these cells were highly responsive to human Sm-C/IGF-I with respect to both [3H]thymidine and [35S]sulfate incorporation, indices of mitotic and differentiated cell functions, respectively. Similarly, both rabbit articular and growth plate chondrocytes showed enhanced incorporation of [3H] thymidine and [35S]sulfate in the presence of Sm-C/IGF-I, but did not respond to either native or recombinant hGH. Cells at different stages of maturation within the bovine growth plate differed in their reaction to Sm-C/IGF-I with proliferative zone cells manifesting a greater response to the peptide than cells of the reserve zone. These results suggest that the action of Sm-C/IGF-I on growth plate and articular chondrocytes is direct and that the effect of GH on these cells is indirect. The data further suggest that within the growth plate, the transition from reserve to proliferative status is associated with an increased Sm-C/IGF-I responsiveness, a change which may contribute to the functional differences in these cells.

Animals↗
PubMed1990

Mechanism of action of parathyroid hormone-induced proteoglycan synthesis in the growth plate chondrocyte.

In the growth plate chondrocyte, parathyroid hormone (PTH) stimulates phosphoinositol 4,5 bisphosphate (PIP2) degradation, which results in the rapid production of inositol (1,4,5) triphosphate (IP3). IP3 induced the release of calcium from an intracellular store, which caused a rapid increase in the cytosolic ionized calcium concentration. Parathyroid hormone also induced a 30-50% increase in proteoglycan synthesis. Phorbol esters, which pharmacologically activate protein kinase C, resulted in a 70-80% increase in proteoglycan synthesis. Treatment of the chondrocytes with retinoic acid (0.2 microM) inhibited the parathyroid hormone and phorbol ester-induced increase in intracellular ionized calcium and the increase in proteoglycan synthesis. From this data we postulate that the stimulation of proteoglycan synthesis in growth plate chondrocytes by PTH is mediated by the breakdown of membrane phosphoinositides, which results in the production of IP3 and an increase in ionized intracellular calcium. It is suggested that the degradation of membrane phosphoinositides also results in production of diacylglycerol and, thereby, an activation of protein kinase C, which has a large stimulatory effect on proteoglycan synthesis. The increase in cytosolic calcium most likely acts synergetically with diacylglycerol to activate protein kinase C. Retinoic acid blocks the effect of PTH and phorbol ester-induced proteoglycan synthesis and may act through the inhibition of protein kinase C. The overall effect of PTH on the growth plate chondrocyte appears to be a stimulation of proteoglycan synthesis that is mediated by the degradation products of membrane phosphoinositides.

Animals↗
PubMed1986

Computed tomography of partial growth plate arrest: initial experience.

Twelve growth plates in 11 patients with clinical evidence of partial growth plate tethering underwent thin slice (1.5 mm) axial high resolution computed tomography (CT), or direct coronal CT. The normal epiphyseal plate was readily visualised as a low density layer of soft tissue density between adjacent sclerotic margins of epiphysis and metaphysis. Two growth plates had greater than 50% obliteration and ten had partial obliteration. Our preliminary results show excellent correlation between the CT findings and surgical pathology. We expect that CT will replace polytomography in the operative evaluation of partial growth plate arrest, as it has in our institution.

Adolescent↗
PubMed2004

Expression of proinflammatory cytokines and growth factors at the injured growth plate cartilage in young rats.

Growth plate, a cartilage-like tissue responsible for bone lengthening in children, has limited abilities to regenerate. After injury, a bony repair often occurs at the injury site, which may lead to growth arrest or angulation of the involved long bone. Our previous study has demonstrated inflammatory, fibrogenic, and osteogenic responses at the injured growth plate; however, the underlying mechanisms remain unclear. In this study, mRNA expression patterns of pro-inflammatory cytokines, growth factors, transcription factors, and matrix proteins were examined by quantitative RT-PCR over a 35-day time period after a drill-hole injury at the proximal tibial growth plate of young rats. During the initial inflammatory phase, IL-1beta expression peaked at 8-16 h, and TNF-alpha and TGF-beta1 levels peaked on day 1. During the subsequent fibrogenic response, expression of growth factors FGF-2 and PDGF-B was up-regulated on day 3 whereas levels of collagen-2a and transcription factor Sox9 remained unchanged. In the osteogenic and bone remodeling stages, levels of TNF-alpha, FGF-2, and TGF-beta1 rose again during days 25-35, and IGF-I and bone matrix protein osteocalcin elevated from days 7 to 35. The positive changes in expression of IL-1beta, TNF-alpha, TGF-beta1, and IGF-I suggest their possible roles in the early acute inflammatory event and later in the formation and remodeling of the bone bridge. The up-regulation of FGF-2 and PDGF-B, coinciding with mesenchymal cell infiltration, suggests their possible involvement in the intermediate fibrogenic response. The lack of up-regulation of Col-2a and Sox9 refutes the involvement of endochondral ossification but confirms a direct bone formation response during bone bridge formation at the injured growth plate.

Age Factors↗
PubMed1990

Synergistic effect of transforming growth factor beta and fibroblast growth factor on DNA synthesis in chick growth plate chondrocytes.

Transforming growth factor beta and fibroblast growth factor are mitogens for chick growth plate chondrocytes. TGF-beta stimulated a 3.5-fold increase, and FGF a 13.5-fold increase in the rate of thymidine incorporation after a 24 h exposure. TGF-beta and FGF were synergistic in chondrocytes, causing a 73-fold stimulation in thymidine incorporation compared with control. This synergistic response was not dependent upon the simultaneous presence of both mitogens. Sequential exposure of chondrocytes to TGF-beta and FGF in either order reproduced in large part the synergistic interaction observed when both growth factors were present simultaneously. The time required for induction of the subsequent synergistic response was brief and, in the case of TGF-beta, corresponded to the time required for [125I]TGF-beta receptor binding. EGF and PDGF were not mitogenic for chondrocytes, and neither of these factors enhanced the response of the cells to either TGF-beta or FGF. Finally, TGF-beta and FGF did not, either alone or in combination, elevate intracellular cAMP levels. These results emphasize the importance of examining growth factor effects in the context of other growth regulators. Furthermore, this specific and dramatic synergistic stimulation of thymidine incorporation may provide a useful tool in elucidating the mitogenic mechanism of the individual growth factors.

Animals↗
PubMed1994

Uptake of [99mTc]technetium methylene diphosphonate in the growth plates of the rabbit tibia during the final part of epiphyseal growth activity.

Uptake of 99mTc-MDP was measured in the proximal and distal growth plate of the rabbit tibia during the final phase of growth. Scintigraphic data were compared with roentgenographically measured tibial length and signs of bony fusion of the growth plates. Uptake by the proximal tibial growth plate was higher than in the distal tibial plate. Uptake decreased on cessation of growth and during subsequent bony fusion. In particular in the proximal tibial region, uptake was still high after cessation of longitudinal growth, which illustrates that during the final period of growth uptake of 99mTc-MDP by a roentgenographically still open growth plate does not necessarily indicate that such a growth plate still contributes to longitudinal growth. Decrease in uptake during the final phase of growth should be considered, when bone scanning is part of a research protocol.

Animals↗
PubMed1991

The repair of full-thickness articular cartilage defects. Immune responses to reparative tissue formed by allogeneic growth plate chondrocyte implants.

Growth plate cartilage cultivated in vitro was attached with a fibrin clot to a full-thickness articular cartilage defect on knee joints in allogeneic New Zealand rabbits. The healing of the defects was assessed by gross examination, light microscopy, and immunologic analysis for 24 weeks. Immunologic assessment of cell-mediated immunity, cytotoxicity of a humoral antibody by a 51chromium release assay, and immunofluorescence studies were carried out. During the first two weeks following grafting, healing was excellent in 11 of the 17 defects. From three to 24 weeks, 11 of 42 defects examined had good results. Host lymphocytes had accumulated around the allograft at two to 12 weeks. Most of the implanted cartilage grown in vitro died and was replaced by fibrous tissue. The immunologic studies suggested that the implanted cartilage began to degenerate two to three weeks after implantation partially because of a humoral immune response but more importantly because of cell-mediated cytotoxicity.

Animals↗
PubMed2003

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

Glucocorticoids cause significant growth retardation in mammals and humans and decreased proliferation of chondrocytes has been considered as the main local mechanism. Death by apoptosis is an important regulator of homeostasis in multicellular organisms. Here we chose to study the role of apoptosis in growth retardation caused by glucocorticoid treatment. We treated 7-week-old male rats with dexamethasone (5 mg/kg/day) for 7 days. Apoptosis was studied in tibiae growth plates by the TUNEL method. Immunoreactivity for parathyroid hormone-related peptide (PTHrP), caspase-3, and the anti-apoptotic proteins Bcl-2 and Bcl-x was also studied. Apoptosis was mainly localized in terminal hypertropic chondrocytes (THCs) in both control and dexamethasone-treated animals. Dexamethasone caused an increase in apoptosis which was fourfold in THCs (2.45+/-0.12 vs 0.62+/-0.09 apoptotic cells/mm growth plate, P<0.001), and 18-fold in proliferative chondrocytes (0.18+/-0.04 vs 0.01+/-0.007 apoptotic cells/mm growth plate, P<0.001). Increased apoptosis after dexamethasone treatment was accompanied by increased immunoreactivity for caspase-3 and decreased immunoreactivity for the anti-apoptotic proteins Bcl-2 and Bcl-x, which further supports our apoptosis results. Dexamethasone also decreased the immunoreactivity for PTHrP, suggesting a role in the mechanism by which glucocorticoids induce apoptosis in the growth plate. We conclude that apoptosis is one mechanism involved in growth retardation induced by glucocorticoids. Premature loss of resting/proliferative chondrocytes by apoptosis could contribute to incomplete catch-up seen after prolonged glucocorticoid treatment.

Animals↗
PubMed1994

[The epiphyseal involvement of metaphyseal bone sarcomas in patients with fertile growth plates. A magnetic resonance assessment].

The growth plate is thought to be capable of limiting tumor spread. To assess the presence and extent of epiphyseal involvement in bone tumors, the plain radiographs and the MR images of 41 patients with metaphyseal sarcoma and radiographically apparent growth plate were studied. The results were compared with surgical, microscopic and histologic findings. Histology demonstrated that in 3 patients the tumor did not reach the growth plate, in 25 the epiphysis was involved while in 13 cases the tumor reached the physis but did not spread to the epiphysis. In the latter group of patients, histology demonstrated a microinfiltration of the physis in 5 cases. Radiography and MR sensitivities were 77.2% and 100%, respectively, while specificity was 94% for both methods. Histology showed that the epiphysis was involved in 25/41 cases (61%) and the growth plate in 30/41 (73%). Our results show that the growth plate does not usually act as a barrier against tumor spread and that MRI is the diagnostic tool of choice in the assessment of epiphyseal spread in metaphyseal tumors even though it cannot detect growth plate microinfiltrations.

Adolescent↗
PubMed1992

Control of protein and matrix-molecule synthesis in isolated ovine fetal growth-plate chondrocytes by the interactions of basic fibroblast growth factor, insulin-like growth factors-I and -II, insulin and transforming growth factor-beta 1.

Chondrogenesis is thought to be controlled by interactions between circulating anabolic hormones and locally produced peptide growth factors, and involves ordered changes in matrix composition which ultimately allow endochondral calcification. We have used a model of isolated ovine fetal growth-plate chondrocytes to examine the actions and interactions of basic fibroblast growth factor (basic FGF), insulin-like growth factors-I and -II (IGF-I and -II), insulin and transforming growth factor-beta 1 (TGF-beta 1) on total protein, collagen or non-collagenous protein and sulphated glycosaminoglycan synthesis. These parameters were determined by assessment of the incorporation by monolayer cultures of early passage chondrocytes of [3H]leucine, [14C]proline and [35S]sulphate respectively, followed by partial molecular characterization. Basic FGF enhanced total protein synthesis with a half-maximal effective concentration of 270 +/- 60 pmol/l (mean +/- S.E.M., four animals) and was sixfold more active on a molar basis than IGF-I or insulin, and 28-fold more active that IGF-II which is the endogenously synthesized IGF. The actions of basic FGF were additive to those of IGF-I or insulin. More detailed analysis of extracellular-matrix component synthesis showed that basic FGF, IGF-I and insulin each caused significant increases in the synthesis of collagen and sulphated glycosaminoglycans. TGF-beta 1 had no effect on total protein synthesis by chondrocytes when present alone at concentrations of 200 pmol/l or less, but was inhibitory at 400 pmol/l. However, the use of this parameter masked a stimulatory action of 50 or 100 pmol TGF-beta 1 on sulphated glycosaminoglycan synthesis and a relative shift in the ratio of collagen: non-collagenous protein synthesis in favour of the former. A synergistic interaction existed between TGF-beta 1 (20-100 pmol/l) and basic FGF which potentiated total protein and collagen synthesis, and their actions on sulphated glycosaminoglycan production were additive. The same concentrations of TGF-beta 1 inhibited the ability of IGF-I or insulin to stimulate total protein or collagen synthesis, but were additive to their stimulatory effects on sulphated glycosaminoglycan synthesis. The results suggest that matrix-molecule composition and the anabolic status of the epiphyseal growth-plate may be modulated in utero by multiple interactions between peptide growth factors produced locally, such as basic FGF, IGF-II and TGF-beta 1, and circulating hormones such as insulin and IGF-I.

Animals↗
PubMed1992

Cell cycle-dependent localization of immunoreactive basic fibroblast growth factor to cytoplasm and nucleus of isolated ovine fetal growth plate chondrocytes.

Basic fibroblast growth factor (basic FGF) is a potent mitogen for chondrocytes in vitro and is present in developing cartilage in vivo. Studies of intracellular basic FGF localization in other cell types have revealed a transient nuclear presence. We have examined ovine fetal growth plate chondrocytes for the presence of intracellular basic FGF by immunocytochemistry. Chondrocytes were isolated from the proximal tibial growth plate of lamb fetuses between 75 and 80 days' gestation using collagenase, and were cultured in monolayer before use between passages 3 and 6. In non-synchronized cell cultures 58 +/- 6% of cells (mean +/- s.d., n = 3) demonstrated cytoplasmic staining for immunoreactive basic FGF. Of these cells, 18 +/- 3% also exhibited strong nuclear staining. Chondrocytes were growth-restricted and restarted into the cell cycle with 2% (vol/vol) fetal calf serum. The timing of S phase was followed by nuclear labelling of nuclei with [3H] thymidine followed by autoradiography, or by the incorporation of [3H] thymidine into trichloroacetic acid-precipitable DNA in parallel cultures. A cytoplasmic presence of immunoreactive basic FGF did not appear, following immunocytochemistry, until the second half of G1 with 97% of cells immunopositive 2 hr prior to S phase. Nuclear staining for basic FGF appeared 2 hr before peak nuclear labelling index, and 56% of cell nuclei were immunopositive. Following entry into S phase cytoplasmic and nuclear basic FGF immunostaining rapidly disappeared. When these experiments were repeated with or without the presence of anti-basic FGF antibody or heparin, the presence of the antibody significantly reduced peak [3H] thymidine incorporation into DNA during S phase while exposure to heparin increased this. However, the proportion of cells demonstrating cytoplasmic or nuclear staining for immunoreactive basic FGF, and the time of onset of staining, were unaltered. Incubation of cells with suramin blocked subsequent DNA synthesis and no intracellular basic FGF was visualized. Cell-conditioned culture medium, extracellular matrix and cytoplasm from synchronized cultures of chondrocytes were taken at time points throughout the cell cycle and assessed for basic FGF content by radioimmunoassay. Basic FGF was detectable in each compartment and steadily rose throughout the second half of G1 to reach maximum values around the S phase. The accumulation of basic FGF in medium, matrix and cytoplasm was blocked by the presence of cycloheximide.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Cell cycle analysis of proliferative zone chondrocytes in growth plates elongating at different rates.

Regulation of postnatal growth of long bones occurs in multiple levels of chondrocytic activity, including stem cell proliferation, proliferative zone cycling, and regulation of changes in chondrocytic shape during hypertrophy. The differentiation sequence of chondrocytes is the same in all growth plates, but rates of elongation at a single point in time and over a period of time differ widely among individual growth plates, which suggests that the rates of sequential gene activation and suppression in this phenotypic pattern can vary. The purpose of this study was to investigate, directly and in vivo, parameters of the cell cycle of proliferative chondrocytes in growth plates growing at widely different rates at a single point in time in order to analyze the relationship between cell cycle time, including the duration of each phase of the cell cycle (G1, S, G2, and M), and the rate of growth. The experimental design used repeated pulse labeling with bromodeoxyuridine and was analyzed using a regression model of time of pulse label with increasing labeling index. Total cell cycle time was calculated as the inverse of the slope of the relationship of the labeling index and the time between labels. The y intercept was the calculated labeling index at time zero. Multiple comparison contrasts were used to test for individual differences among four growth plates with growth rates ranging from approximately 50 to 400 microns per 24 hours from 28-day-old rats. The estimate of total cell cycle time for the proximal tibial growth plate was 30.9 hours. Cell cycle times for the other three growth plates were 34.0, 48.7, and 76.3 hours for the distal radius, distal tibia and proximal radius, respectively. Although the times for the proximal tibia and distal radius did not differ significantly, all other times were significantly different (p < 0.05). Almost all differences in total cell cycle time were attributable to significant differences in the length of the G1 phase. The S phase was estimated at 3.4-6.1 hours; the G2 phase, at 3.0 hours; and the M phase, at 0.5-0.6 hours. The current study suggests that regulation through cell cycle parameters, specifically in the G1 phase, may be involved in overall regulation of differential postnatal long bone growth. It has previously been established that increase and shape change of cellular volume during hypertrophy may be regulated at the level of individual growth plates and that both are significant in understanding differential growth of long bone at this level. By demonstrating that chondrocytes in the proliferating zone have different cell cycle times that are regulated primarily through differences in the duration of G1, this study suggests that, in addition to systemic controls of chondrocyte proliferation, local controls may modulate rates of proliferation of individual growth plates and thus may be another locally mediated regulator of differential growth.

Animals↗
PubMed2006

Roles of neutrophil-mediated inflammatory response in the bony repair of injured growth plate cartilage in young rats.

Injured growth plate cartilage is often repaired by bony tissue, resulting in impaired bone growth in children. Previously, injury-induced, initial inflammatory response was shown to be an acute inflammatory event containing predominantly neutrophils. To examine potential roles of neutrophils in the bony repair, a neutrophil-neutralizing antiserum or control normal serum was administered systemically in rats with growth plate injury. The inflammatory response was found temporally associated with increased expression of neutrophil chemotactic chemokine cytokine-induced neutrophil chemoattractant-1 and cytokines TNF-alpha and IL-1beta. Following the inflammatory response, mesenchymal infiltration, chondrogenic and osteogenic responses, and bony repair were observed at the injury site. Neutrophil reduction did not significantly affect infiltration of other inflammatory cells and expression of TNF-alpha and IL-1beta and growth factors, platelet-derived growth factor-B and TGF-beta1, at the injured growth plate on Day 1 and had no effects on mesenchymal infiltration on Day 4. By Day 10, however, there was a significant reduction in proportion of mesenchymal repair tissue but an increase (although statistically insignificant) in bony trabeculae and a decrease in cartilaginous tissue within the injury site. Consistently, in antiserum-treated rats, there was an increase in expression of osteoblastic differentiation transcription factor cbf-alpha1 and bone matrix protein osteocalcin and a decrease in chondrogenic transcription factor Sox-9 and cartilage matrix collagen-II in the injured growth plate. These results suggest that injury-induced, neutrophil-mediated inflammatory response appears to suppress mesenchymal cell osteoblastic differentiation but enhance chondrogenic differentiation, and thus, it may be involved in regulating downstream chondrogenic and osteogenic events for growth plate bony repair.

Animals↗
PubMed1992

Interaction of basic fibroblast growth factor with bovine growth plate chondrocytes.

The basic fibroblast growth factor (bFGF) family of peptides influences a wide range of cellular actions. To better understand the possible role of bFGF in the growth plate, we have characterized the interaction of this growth factor with isolated bovine growth plate chondrocytes. Basic FGF interacts with two classes of binding sites on these cells. One is consistent with high-affinity bFGF receptors and the other with low-affinity heparin-like binding sites on the chondrocyte surface. Radiolabeled bFGF binding studies revealed approximately 4 x 10(6) binding sites per cell, with a Kd of approximately 42 nM. Graded concentrations of heparin or NaCl competed with [125I]-labeled bFGF in a dose-dependent fashion, reducing [125I]-labeled bFGF binding by 75 and 97%, respectively. The data suggest the presence of a high-capacity, low-affinity class of binding sites with the properties of a heparin-like moiety. Affinity cross-linking of [125I]-labeled bFGF to chondrocytes labeled two principal species with apparent molecular masses of 135 and 160 kDa. Labeled bFGF was specifically displaced from both species by subnanomolar concentrations of unlabeled bFGF. These high-affinity, low-capacity binding sites are characteristic of classical bFGF receptors. Binding of [125I]-labeled bFGF to these sites was also influenced by heparin, consistent with coregulation of binding to the two classes of binding sites. The data suggest that bFGF participates in the regulation of skeletal growth at the growth plate and that this regulation may involve bFGF interaction with at least two distinct classes of binding sites.

Animals↗
PubMed2001

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.

Animals↗