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PubMed1995

Growth hormone and IGF-I stimulate cell function in distinct zones of the rat epiphyseal growth plate.

Proliferation and maturation of growth plate chondrocytes are primarily responsible for linear bone elongation, although the exact mechanisms involved have not been fully characterized. We have used discrete chondrocyte populations to address the mode of growth hormone (GH) action on the growth plate. Low doses of GH, and insulin-like growth factor-I (IGF-I) preferentially enhanced cell proliferation in proliferative zone chondrocytes; the mitogenic response of immature proliferative and resting zone cells was minimal. Proliferation was not enhanced by combining the effects of GH and IGF-I. Exposure to IGF-I increased IGF-I mRNA in resting zone cells. Both GH and IGF-I stimulated the accumulation of IGF-I receptor mRNA in the most immature proliferative zone cells but did not alter the accumulation of IGF-binding protein 4 mRNA in any fraction. These results confirm a direct effect of GH on growth plate chondrocytes and suggest that GH preferentially acts on the actively proliferating chondrocytes.

Animals↗

PubMed2000

MR imaging of changes of the growth plate after partial physeal removal and fat graft interposition in rabbits.

RATIONALE AND OBJECTIVES: The most important complication of skeletal injuries involving the growth plate is growth disturbance. The purpose of this study was to evaluate MR features of growth plate modification after fat graft interposition in growth plate injury and to correlate these findings with pathological findings. METHODS: A growth plate injury model was used in 12 skeletally immature rabbits. A longitudinal drill hole 5 mm in diameter was created in the central part of the growth plate in the distal femur, bilaterally. One side was filled with autologous fat, and the contralateral defect was left empty as a control. Magnetic resonance imaging was obtained 1, 3, and 6 months after surgery, and routine histological study was performed. The authors evaluated sequential changes in MR images and the histological basis of MR findings. RESULTS: In grafted femur, the signal intensity of the grafted area was lower than that of the surrounding bone on T2-weighted images at 1 month. The growth plate defect at 3 to 6 months was modified and had a proximally tapering appearance. The ratio of the growth plate defect was smaller in the grafted femur than in the control femur after surgery. Histologically, the fat-grafted area was replaced by fibrous connective tissue. In the control femur, a bony bridge was rectangular in the longitudinal direction and showed isosignal intensity with a rim of low signal intensity on T1-weighted imaging. Histologically, the defect was filled with mature fatty marrow with new bone formation in the control femur. CONCLUSIONS: The proximally pointing appearance and the low signal intensity of the grafted area on MR suggested fibrous degeneration of grafted fat that prevented solid bony bridge formation in experimentally induced growth plate injury.

Adipose Tissue↗

PubMed1995

Immunoelectron microscopic analysis of chondroitin sulfates during calcification in the rat growth plate cartilage.

The proximal growth plate cartilage of rat tibia was fixed in the presence of ruthenium hexamine trichloride (RHT) in order to preserve proteoglycans in the tissue. Quantitative changes of chondroitin sulfates during endochondral calcification were investigated by immunoelectron microscopy using mouse monoclonal antibodies 1-B-5, 2-B-6, and 3-B-3, which recognize unsulfated, 4-sulfated, and 6-sulfated chondroitin sulfates, respectively. The content of chondroitin-4-sulfate in the cartilage matrix increased from the proliferative zone to the calcifying zone, while that of unsulfated chondroitin sulfate decreased. Chondroitin-6-sulfate remained constant from the proliferative zone to the upper hypertrophic zone, then decreased in the calcifying zone. The immunoreaction to each antibody increased conspicuously in the cartilagenous core of metaphysial bone trabeculae. The changes of sulfation in chondroitin sulfate chains of proteoglycans may play an important role in inducing and/or promoting calcification in growth plate cartilage.

Animals↗

PubMed1990

Growth plate physiology and pathology.

The growth plate is made of cartilaginous, bony, and fibrous components, which act together to achieve longitudinal bone growth. The unique metabolism of the growth plate is a result of its unique microcirculation and extracellular microenvironment. The growth plate chondrocytes are responsive to both mechanical and hormonal stimuli, which can alter their normal function. Pathologic states result from environmental, hormonal, nutritional, and genetic factors.

Animals↗

PubMed1990

Cytosolic free calcium concentrations in avian growth plate chondrocytes.

Isolated avian growth plate chondrocytes convert the acetoxymethyl ester (AM) form of Fura-2 quickly and efficiently to the Ca2(+)-sensitive pentacarboxylic acid (FA) form. Control experiments indicate that the Kd for intracellular Fura-2/FA is very close to that of extracellular Fura-2/FA at the same ionic strength and pH and that the Fura-2/FA fluorescence from indicator converted by intracellular organelles is quite small. Correcting for the effects of extracellular Fura-2/FA and partial hydrolysis products has improved the accuracy of determination of intracellular [Ca2+] over earlier measurements in chondrocytes. Cytosolic [Ca2+] in isolated growth plate chondrocytes (containing cells from each maturational stage) is found to require approximately 9 hours to recover from the isolation process. After this recovery period, cytosolic [Ca2+] in these cells converges to approximately 70 nM regardless of the [Ca2+] of the recovery medium, suggesting regulation of cytosolic [Ca2+] to a set point. Chondrocytes that are separated into maturationally distinct fractions using countercurrent centrifugal elutriation show an increase in cytosolic [Ca2+] with cellular maturation. The least mature resting cells have a [Ca2+] near 57 nM, while the most mature hypertrophic cells are around 95 nM.

Animals↗

PubMed2006

Ossification of the mouse metatarsal: differentiation and proliferation in the presence/absence of a defined growth plate.

There is significant diversity in growth plate behavior among sites within an individual skeleton and between skeletons of different species. This variation within wild-type animals is an underutilized resource for studying skeletal development. One bone that potentially exhibits the most diverse behavior is the metatarsal. While one end forms a growth plate with an epiphyseal secondary center of ossification as in other long bones, the opposite end undergoes direct ossification in a manner more similar to short bones. Although descriptions of human metatarsal/metacarpal ossification are available, a detailed comparative analysis has yet to be conducted in an animal model amenable to biomolecular analysis. Here we report an analysis of proximal and distal ossification in an age series of mouse metatarsals. Safranin O staining was used for qualitative and quantitative histology, and chondrocyte differentiation and proliferation were analyzed using immunohistochemistry for type X collagen and proliferative cell nuclear antigen expression. We establish that, as in the human, both growth plate formation and direct ossification occur in the mouse metatarsal, with chondrocyte populations showing distinct differentiation patterns at opposite ends of the bone. In addition, growth plate formation is characterized by a peak of proliferation in reserve zone chondrocytes that distinguishes it from both established growth plates and direct ossification. Our analysis demonstrates that the mouse metatarsal is a productive model for investigating natural variation in ossification that can further understanding of vertebrate skeletal development and evolution.

Animals↗

PubMed1994

Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo.

Skeletal growth depends upon enchondral ossification in growth plate cartilage, within which chondrocytes undergo well defined stages of maturation. We infused IGF-I or growth hormone (GH), two key regulators of skeletal growth, into hypophysectomized rats and compared their effects on growth plate chondrocyte differentiation using qualitative and quantitative autoradiography, stereology, and incident light fluorescence microscopy. Stem cell cycle time was shortened from 50 to 15 and 8 d after treatment with IGF-I and GH, respectively. Proliferating cell cycle time decreased from 11 to 4.5 and 3 d, and duration of the hypertrophic phase decreased from 6 to 4 and 2.8 d. Average matrix volume per cell at each differentiation stage was similar for normal, hormone-treated, and untreated hypophysectomized groups. Mean cell volume and cell height were significantly reduced by hypophysectomy at the proliferative and hypertrophic stages, but were restored to physiological values by IGF-I and GH. In contrast, cell productivity, i.e., increases in cell volume, height, and matrix production per unit of time, did not reach normal values with either IGF-I or GH, and this parameter was inversely proportional to cell cycle time or phase duration. IGF-I and GH are thus capable of stimulating growth plate chondrocytes at all stages of differentiation, albeit to variable degrees with respect to individual cell activities. Although it is generally accepted that GH acts at both the stem and proliferating phases of chondrocyte differentiation, our data represent the first evidence in vivo that IGF-I is also capable of stimulating stem cells.

Animals↗

PubMed1995

Role of heparan sulfate in the terminal differentiation of growth plate chondrocytes.

Recent studies have demonstrated that basic fibroblast growth factor (bFGF) plays a key role in the terminal differentiation of growth plate chondrocytes during endochondral ossification. In this paper we examined the potential role of heparan sulfate in the regulation of the action of basic fibroblast growth factor (bFGF) in the terminal differentiation of rat growth plate chondrocytes. As rat growth plate chondrocytes differentiate in vitro, the percentage of heparitinase-sensitive material decreases. Treatment of growth plate chondrocytes with sodium chlorate, a reversible inhibitor of glycosaminoglycan sulfation, resulted in terminal differentiation of growth plate chondrocytes even in the presence of bFGF at concentrations that normally repress their differentiation. Chlorate treatment in the presence of bFGF resulted in an increase in alkaline phosphatase activity and a decrease in cellular proliferation, both characteristics of the differentiated state. Chlorate treatment also reduced the binding of bFGF to growth plate chondrocytes and this effect could be reversed in a dose-dependent manner by the simultaneous addition of sodium sulfate. The reduced binding was a function of a reduced number of receptors and not a reduced affinity for the receptor. Pretreatment of the growth plate chondrocytes with heparitinase significantly reduced the binding of bFGF to both low- and high-affinity receptors, while pretreatment with chondroitinase ABC had no effect. Finally, addition of exogenous heparin restored bFGF binding to chlorate-treated chondrocytes in a concentration-dependent manner. These results provide evidence that a cell surface heparan sulfate is involved in the binding of bFGF to high-affinity receptors and that a downregulation of this glycosaminoglycan is part of the pathway that leads to terminal differentiation of growth plate chondrocytes.

Animals↗

PubMed2006

Cortical bone development under the growth plate is regulated by mechanical load transfer.

Longitudinal growth of long bones takes place at the growth plates. The growth plate produces new bone trabeculae, which are later resorbed or merged into the cortical shell. This process implies transition of trabecular metaphyseal sections into diaphyseal sections. We hypothesize that the development of cortical bone is governed by mechanical stimuli. We also hypothesize that trabecular and cortical bone share the same regulatory mechanisms for adaptation to mechanical loads. To test these hypotheses, we monitored the development of the tibial cortex in growing pigs, using micro-computer tomography and histology. We then tested the concept that regulatory mechanisms for trabecular bone adaptation can also explain cortical bone development using our mechanical stimulation theory, which could explain trabecular bone (re)modelling. The main results showed that, from the growth plate towards the diaphysis, the pores of the trabecular structure were gradually filled in with bone, which resulted in increased density and cortical bone. The computer model largely predicted this morphological development. We conclude that merging of metaphyseal trabeculae into cortex is likely to be governed by mechanical stimuli. Furthermore, cortex development of growing long bones can be explained as a form of trabecular bone adaptation, without the need for different regulatory mechanisms for cortical and trabecular bone.

Adaptation, Physiological↗

PubMed2003

Raloxifene acts as an estrogen agonist on the rabbit growth plate.

Estrogen treatment has been used to induce growth plate fusion, thereby reducing the final height in girls expected to achieve extreme tall stature. The treatment is effective, in terms of limiting final height, but concerns have been raised that it might also increase the risk for malignancies later in life. Raloxifene, a selective estrogen receptor modulator, has been shown to act as an estrogen agonist on bone density but as an estrogen antagonist on breast and uterine tissue. The effect of raloxifene treatment on growth plate fusion and final height is unknown. The aim of this study was to determine whether raloxifene would act as an estrogen agonist or antagonist on growth plate cartilage. Ovariectomized immature rabbits were treated for 4 wk with vehicle (controls), estradiol cypionate (E2), or raloxifene. Tibial growth velocity was decreased in both E2- (P < 0.001) and raloxifene-treated animals (P < 0.001), compared with controls. E2 and raloxifene treatment also decreased chondrocyte proliferation and the height of the proximal tibial growth plate. In addition, E2 and raloxifene hastened fusion of the distal tibial growth plate (P < 0.05) and decreased the number of proliferative and hypertrophic chondrocytes per column in the proximal tibial growth plate. As expected, the uterus was enlarged by estrogen, but not raloxifene, treatment. We conclude that raloxifene acts as an estrogen agonist on the growth plate, accelerating growth plate senescence and thus hastening epiphyseal fusion.

Animals↗

PubMed1995

Fractionation of growth plate chondrocytes: differential expression of IGF-I and growth hormone and IGF-I receptor mRNA in purified populations.

In vitro studies of growth plate cell kinetics have been hindered by the spatial arrangement and heterogeneity of cells within the plate. In this study, we describe a fractionation method that consistently generated five relatively pure populations of growth plate chondrocytes. Each fraction exhibited morphology, proliferative rates, and marker mRNA expression consistent with in vivo positional phenotypes. In characterizing the fractional response, fibroblast growth factor was most effective in stimulating resting cells to proliferate and least effective on cells actively dividing (fraction 3). Insulin-like growth factor-I (IGF-I) was most active on fraction 3 while epidermal growth factor's mitogenic induction was equivalent across all fractions. Growth hormone receptor (GHR) mRNA was most abundant in mature hypertrophic cells and undetectable in resting cells; IGF-I receptor (IGF-IR) mRNA was detectable in resting cells but two-fold higher in the fraction adjacent to cells possessing high GHR mRNA, while proliferating and resting chondrocytes had elevated IGF-I mRNA levels when compared to that for hypertrophic chondrocytes. The growth plate distribution of IGF-IR and GHR mRNA implies distinct roles for circulating IGF-I vs. paracrine produced IGF-I.

Animals↗

PubMed2001

Partial growth plate fusion caused by burn.

Growth plate fusion is a rare but important complication of burn injury in childhood. Reported cases are all of complete fusion. We present a case of partial fusion of the growth plates secondary to a burn injury, which to our knowledge has not been reported in the literature before. Partial fusion of the growth plate behaves differently as compared with complete fusion, and if treated at an early stage by appropriate surgery limb deformity and long-term disability may be prevented. The importance of early recognition and treatment cannot be overemphasized.

Adult↗

PubMed1983

Absence of the glycerol phosphate shuttle in the various zones of the growth plate.

UNLABELLED: The various zones of the growth plate of the rib of six-week-old male New Zealand White rabbits were obtained by means of a specially devised guillotine slicing apparatus. Cartilage slices from each zone were assayed enzymatically for activity of glycerol phosphate dehydrogenase by an adaptation of a fluorimetric technique based on the conversion of non-fluorescent resazurin to the highly fluorescent resorufin in the presence of nicotinamide adenine dinucleotide and the enzyme. No glycerol phosphate dehydrogenase activity was detectable in any zone of the growth plate, whereas control liver slices exhibited abundant enzyme activity. Thus the glycerol phosphate shuttle, one pathway whereby reducing equivalents are carried or shuttled from cytoplasmic nicotinamide adenine dinucleotide to the intramitochondrial respiratory chain, is entirely lacking in growth-plate chondrocytes. The lack of this enzyme, and the absence of the glycerol phosphate shuttle, may explain the high rate of lactate accumulation in the presence of ample oxygen concentration (aerobic accumulation) even though the Krebs cycle (tricarboxylic acid cycle) and electron transport are proceeding at normal rates. CLINICAL RELEVANCE: The growth plate is a complex structure whose metabolism is still not well understood. This study demonstrates that, in at least one metabolic pathway, the growth-plate chondrocyte does not resemble other normal cells. Only as we are able to formulate a more complete picture of the metabolism of the normal growth plate will be able to understand, and perhaps correct or prevent, those disease states in which growth-plate metabolism has bone away.

Animals↗

PubMed1981

Cell production of different growth plates in the rabbit.

In different growth regions of the long bones of normal rabbits the cell production in the growth plates were calculated from values of longitudinal bone growth determined with oxytetracycline and values of the degenerative cell size. The cell production was found to decrease similarly with increasing age for all growth regions. The rate of cell production for the various growth plates differed. There was little influence by age or localization on the size of the degenerative cells in the growth plate. Compared to other species such as rat and man the cell size in the rabbit is almost the same, whereas the difference in growth rate depends mainly on the cell production - mitotic activity - in the growth plate.

Age Factors↗

PubMed2000

Different bone growth rates are associated with changes in the expression pattern of types II and X collagens and collagenase 3 in proximal growth plates of the rat tibia.

Skeletal growth depends on endochondral ossification in growth plate cartilage, where proliferation of chondrocytes, matrix synthesis, and increases in chondrocyte size all contribute to the final length of a bone. To learn more about the potential role of matrix synthesis/degradation dynamics in the determination of bone growth rate, we investigated the expression of matrix collagens and collagenase 3 in tibial growth plates in three age groups of rats (21, 35, and 80 days after birth), each characterized by specific growth rates. By combining stereological and in situ hybridization techniques, it was found that the expression of matrix collagens and collagenase 3 was specifically turned on or off at specific stages of the chondrocyte-differentiation cycle, and these changes occurred as a temporal sequence that varied depending of animal growth rate. Furthermore, the expression of these matrix proteins by a growth plate chondrocyte was found to be sped up or slowed down depending of the growth rate. In addition to expression of types II and X collagen, collagenase-3 expression was found to constitute a constant event in the series of changes in gene expression that takes place during the chondrocyte-differentiation process. Collagenase-3 expression was found to show a biphasic pattern: it was intermittently expressed at the proliferative phase and uniformly expressed at the hypertrophic stage. An intimate relationship between morphological and kinetic changes associated with chondrocyte hypertrophy and changes in the expression pattern of matrix collagens and collagenase 3 was observed. Present data prove that the matrix synthesis/degradation dynamics of the growth plate cartilage varied depending on growth rate; these results support the hypothesis that changes in matrix degradation and synthesis are a critical link in the sequence of tightly regulated events that lead to chondrocytic differentiation.

Animals↗

PubMed1992

Growth plate injuries: Salter-Harris classification.

Fracture of the growth plate is an injury unique to childhood. Most such fractures heal without permanent deformity. A small percentage, however, are complicated by growth arrest and subsequent deformity. The Salter-Harris classification of growth plate injuries aids in estimating both the prognosis and the potential for growth disturbance. The Salter-Harris system classifies growth plate fractures into five groups: type I, fracture through the growth plate; type II, fracture through the growth plate and metaphysis; type III, fracture through the growth plate and epiphysis; type IV, fracture through the growth plate, epiphysis and metaphysis, and type V, crush or compression injury of the growth plate.

Biomechanical Phenomena↗

PubMed2001

The parathyroid hormone-related protein and Indian hedgehog feedback loop in the growth plate.

Normal development of the growth plate requires coordinated proliferation and differentiation of chondrocytes and osteoblasts. In previous work, we have shown that Indian hedgehog (IHH), produced by prehypertrophic and hypertrophic chondrocytes, stimulates production of parathyroid hormone-related protein (PTHrP) by perichondrial and early chondrocytic cells. PTHrP then maintains chondrocytes in a proliferative, less differentiated state. Because this less differentiated state delays the production of IHH, IHH and PTHrP may participate in a negative feedback loop that synchronizes and determines the pace of differentiation of chondrocytes in the growth plate. To establish the roles of physiological levels of PTHrP and IHH, we have now injected PTH/PTHrP receptor (-/-) embryonic stem (ES) cells into normal blastocysts to generate mice with chimeric growth plates. The PTH/PTHrP receptor cells leave the proliferative cycle and differentiate prematurely in the middle of the normal proliferative columns. The columns of wild-type cells are longer than normal and the adjacent bone collar is also longer than normal. Patterns of gene expression and the use of chimeras using PTH/PTHrP receptor (-/-); IHH (-/-) ES cells suggest that modified patterns of IHH and PTHrP synthesis explain these abnormalities. Thus, IHH is a master regulator of both chondrocyte and osteoblast differentiation.

Animals↗

PubMed1997

Expression of growth factors in chicken growth plate with special reference to tibial dyschondroplasia.

Immunoreactive growth factors were identified in chick embryonic cartilage and bone, and in the growth plate of normal tibiotarsi and tibiotarsi affected with tibial dyschondroplasia (TD). A specific pattern of temporal and spatial expression was observed for each growth factor. Transforming growth factor beta and alpha (TGF beta and TGF alpha) and epidermal growth factor (EGF) were briefly expressed in chondrocytes of early chick embryos. Immunolabelling for TGF beta then gradually shifted into cartilaginous matrix and was not observed in cytoplasm of hypertrophic chondrocytes until the late embryonic and post-hatch stages. The distribution and intensity of TGF beta labelling was the same in chondrocytes of the TD and normal growth plate. Insulin-like growth factor I (IGF-I) labelling persisted from the early embryonic stage to the end of the mid-stage and then disappeared from chondrocytes. IGF-I appeared again in chondrocytes 1-2 days before hatching. After hatching, the labelling intensified in prehypertrophic and hypertrophic chondrocytes. TD lesions displayed IGF-I in the distal region, mainly in chondrocytes around small blood vessels. EGF reappeared in proliferative and hypertrophic chondrocytes of the mid-embryonic stage. By day 18 after hatching, EGF was present mainly in prehypertrophic and hypertrophic chondrocytes. EGF was demonstrated only in distal proliferative and early prehypertrophic chondrocytes of the dyschondroplastic growth plate. TGF alpha was identified in hypertrophic chondrocytes adjacent to the periosteum and in the distal tip of the mid-embryonic growth plate. With progressing ossification, TGF alpha labeling intensified in the embryonic hypertrophic chondrocytes. In the TD growth plate at day 18 after hatching, TGF alpha expression was limited to 1-3 concentric layers of chondrocytes surrounding blood vessels.

Animals↗