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PubMed1987

Quantitation of chondrocyte performance in growth-plate cartilage during longitudinal bone growth.

The longitudinal growth of bone depends on the activities of individual chondrocytes of the growth plate. Each chondrocyte remains in a fixed location throughout its life, and there accomplishes all of its functions. Although a cell may perform several or all of its activities simultaneously, one of these will usually predominate during a particular phase of its life. The two most prominent stages are those of cellular proliferation and hypertrophy (including the mineralization of matrix) before the resorption of tissue during vascular invasion. By applying recently developed stereological procedures and improved methods for the fixation of cartilage, we compared cellular shape modulation, various ultrastructural parameters (surface areas or volumes of endoplasmic reticulum, Golgi membranes, and mitochondria), the production of matrix, and cellular turnover for proliferating and hypertrophic chondrocytes within the proximal tibial growth plate of the rat. By the late hypertrophic stage, fourfold and tenfold increases in the mean cellular height and volume, respectively, and a threefold increase in the mean volume of the matrix per cell were achieved. The high metabolic activity of hypertrophic cells was reflected by a twofold to fivefold increase in the mean cellular surface area of rough endoplasmic reticulum, the Golgi membranes, and the mean cellular mitochondrial volume. Rates of longitudinal growth were determined by fluorochrome labeling and incident-light fluorescence microscopy. Using these values and the stereological estimators describing cellular height, the rates of cellular turnover were calculated. The rapid progression of the vascular invasion front was found to eliminate, for each column of cells, one chondrocyte every three hours; that is, eight cells a day. The maintenance of a steady-state structure for growth-plate cartilage in rats in a steady state of growth thus necessitates efficient compensation for these losses, which is achieved by a high rate of cellular proliferation and rapid hypertrophy.

Animals↗
PubMed2004

Expression of SHOX in human fetal and childhood growth plate.

Abnormalities in the growth plate may lead to short stature and skeletal deformity including Leri Weil syndrome, which has been shown to result from deletions or mutations in the SHOX gene, a homeobox gene located at the pseudoautosomal region of the X and Y chromosome. We studied the expression of SHOX protein, by immunohistochemistry, in human fetal and childhood growth plates and mRNA by in situ hybridization in childhood normal and Leri Weil growth plate. SHOX protein was found in reserve, proliferative, and hypertrophic zones of fetal growth plate from 12 wk to term and childhood control and Leri Weil growth plates. The pattern of immunostaining in the proliferative zone of childhood growth plate was patchy, with more intense uniform immunostaining in the hypertrophic zone. In situ hybridization studies of childhood growth plate demonstrated SHOX mRNA expression throughout the growth plate. No difference in the pattern of SHOX protein or mRNA expression was seen between the control and Leri Weil growth plate. These findings suggest that SHOX plays a role in chondrocyte function in the growth plate.

Adolescent↗
PubMed2005

Non-uniform strain distribution within rat cartilaginous growth plate under uniaxial compression.

Growth plates are highly inhomogeneous in morphology and composition. Mechanical loading can modulate longitudinal bone growth, though the mechanisms underlying this mechanobiology are poorly understood. The proximal tibial growth plates of six rats were tested in vitro under uniaxial compression to 5% strain, and confocal microscopy was used to track and capture images of fluorescently labeled cell nuclei with increasing applied strains. The local strain patterns through the growth plate thickness were quantified using texture correlation analysis. The technique of texture correlation analysis was first validated by comparing theoretical simulated strain maps generated from numerically distorted images. The texture correlation algorithm was sensitive to the grid size superimposed on the original image, but remained insensitive to parameters related to the size of the final image mask, which was searched by the correlation algorithm for each grid point of the original image. Within the growth plate, experimental strain distributions were non-uniform in all six specimens. Growth plates were mostly under compression strains. The strain distributions differed among the histomorphological zones of the growth plate, which was most obvious in specimens with regular growth plate shape: higher compressive strains (4-8 times higher than the applied 5% strain) were located mainly in regions overlapping the reserve and hypertrophic zones with lower compressive strains in the proliferative zone. This study documents the non-uniform mechanical behavior of growth plate across its three histological zones when exposed to compression. Further investigation is required to establish the significance of non-uniform strain fields during growth in vivo.

Algorithms↗
PubMed1994

Induction of growth plate cartilage ossification by basic fibroblast growth factor.

In mammals, longitudinal bone growth results from the precise coupling of chondrogenesis and osteogenesis within the epiphyseal growth plate, a process termed endochondral ossification. The mechanisms coupling chondrogenesis and osteogenesis are unknown. Previous studies have shown that both basic fibroblast growth factor (bFGF) and acidic FGF are expressed by growth plate chondrocytes. Here we show that bFGF, infused directly into the rabbit proximal tibial growth plate, accelerates vascular invasion and ossification of growth plate cartilage. Our results suggest the possibility that bFGF (or a related member of the FGF family) couples osteogenesis to chondrogenesis by attracting vascular and bone cell invasion from the adjacent metaphyseal bone.

Animals↗
PubMed2005

Spatial distribution of growth hormone receptor, insulin-like growth factor-I receptor and apoptotic chondrocytes during growth plate development.

Linear bone growth depends upon proliferation, maturation, and apoptosis of growth plate chondrocytes, processes regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I). To investigate the contribution of GH, IGF-I and apoptosis to growth plate function, the expression of GH receptor (GHR) and IGF-I receptor (IGF-IR) mRNA were evaluated by in situ hybridization in fractionated costochondral growth plates of growing rats (at 2, 4, and 7 weeks). Apoptosis was determined by TUNEL assay and morphology in histological sections. GHR mRNA was greatest in resting cells with hypertropic cells increasing GHR expression with increasing age. Hypertropic and resting cell IGF-IR mRNA declined over the ages studied. Receptor mRNA expression was altered by exposing cells to GH or IGF-I. GH and IGF significantly decreased GHR mRNA in proliferative cells. GH and IGF also decreased IGF-IR mRNA in resting cells and the 2- and 4-week-old proliferative and hypertropic cells. Treating cells in culture with GH increased the number of apoptotic cells across all ages and zones. Histologically, apoptotic cells were observed at the chondro-osseous junction and within actively proliferating chondrocytes but not in resting cells. Apoptosis was highest at 4 weeks of age with lateral regions displaying the greatest number of cells undergoing apoptosis. These data indicate that apoptosis plays a role in growth plate function, particularly spatial configuration as indicated by the preferential lateral cell apoptosis. The susceptibility of proliferative cells to GHR and IGF-IR down regulation during the period of greatest apoptosis supports a role for the GH-IGF axis in both proliferation and apoptosis during growth plate development.

Animals↗
PubMed1989

Regeneration of the growth plate.

The occurrence of growth plate regeneration has been doubted. However, in 5 different series of experiments reported between 1950 and 1986 regeneration of injured parts of growth plates in long bones of rabbits and pigs could be demonstrated. The 1st series implied partial X-ray injury of growth plates in rabbits aged 3-6 weeks. The 2nd series implied autotransplantation of the head of the fibula in rabbits aged 10-21 days. The 3rd, 4th and 5th series implied transplantation of autologous fat grafts into provoked defects of growth plates in rabbits and pigs. The findings show that regeneration of a growth plate occurs when a part of it is injured in such a manner that a bone bridge is not formed between the epiphysis and the metaphysis. Regeneration of a plate is much faster in relation to the growth in length of the bone in the rabbit than in the pig. The 1st and 2nd series suggest that regeneration takes place by interstitial proliferation of cells from the germinal layer of the uninjured parts of the plate. Signs of partial regeneration of growth plates have been seen in radiographs after operation for partial closure of growth plates in children.

Adipose Tissue↗
PubMed1997

TGF-beta2 prevents the impaired chondrocyte proliferation induced by unloading in growth plates of young rats.

Growth plate width and cartilage organization are altered during skeletal unloading in growing rats. Immunohistochemical studies have identified TGF-beta in calcified cartilage, and TGF-beta is known to induce mitogenic effects on chondrocytes in vitro. On the other hand, IGF-1 was shown to be expressed in the proximal tibial growth plate and to mediate GH-induced longitudinal bone growth in rats. We therefore investigated the effect of recombinant human (rh) IGF-1 and rhTGF-beta2 infusion on the changes induced by unloading in the cellular organization of the growth plate in growing rats. Hindlimb unloading for 14 days induced a 13% reduction in growth cartilage height in the proximal tibia. This effect was mostly related to a 17% and 14% decrease in the proliferative zone height and chondrocyte number, respectively. In unloaded rats treated with a systemic infusion of rhTGF-beta2 (2microg/kg/day) the number of chondrocytes in the proliferative zone was not different from those of normal loaded animals. In contrast, rhIGF-1 treatment at a 2mg/kg/day dose was not effective in counteracting the effects of unloading on growth plate height and chondrocyte number. These results show that systemic administration of rhTGF-beta2 prevents in large part the reduced growth of chondrocytes in the proliferative zone and the reduced epiphyseal growth plate growth induced by unloading in rats.

Animals↗
PubMed1989

Stereological study of the developing distal femoral growth plate.

The distal femoral growth plate has a uniquely convoluted structure comprised of four mammillate processes. Factors contributing to the development of these processes and overall plate geometry were explored using three-dimensional image analysis of the canine distal femoral epiphysis. The growth plate at birth remains relatively flat until ossification of the epiphysis begins at 1 week of age. Epiphyseal ossification proceeds eccentrically, projecting in the medial-lateral and anterior-posterior directions. Growth plate activity indexed by [3H]thymidine labeling and plate thickness revealed regional differences in cell proliferation. This was measured as a decreased labeling index and thinning of the growth plate in areas capped by the ossifying epiphysis. The eccentric ossification pattern and associated variations in growth plate activity result in definition of an "intraphyseal" groove and medial-lateral oriented sulcus. The groove and sulcus bisect the plate into four quadrants, giving rise to a convoluted structure composed of four areas of plate elevations termed mammillary processes (MP). By 5 weeks, the pattern of ossification results in greater development of the MP in the anterior-medial quadrant and in decreasing order, in the posterior-medial, anterior, and posterior-lateral quadrants. By 10 weeks, a uniform rate of cell proliferation was observed coincident with completion of ossification of the epiphysis. The data suggest that localized variations in growth plate proliferation are associated with ossification of the epiphysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed2005

Hormonal regulation of growth plate cartilage.

Longitudinal bone growth occurs in the growth plate through a process called endochondral bone formation, a process where resting zone chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization. The balance between proliferation and differentiation is a crucial regulatory step controlled by various growth factors/hormones acting in both endocrine and paracrine/autocrine ways. From studies of individuals with aromatase deficiency and a boy with defective oestrogen receptor (ER)-alpha it has become clear that oestrogen action is indispensable for normal pubertal growth and growth plate fusion. Both oestrogen receptors, ER-alpha and ER-beta, are expressed in the growth plate in boys and girls throughout pubertal development. Any functional role of ER-beta has not yet been defined in the human growth plate. Increased understanding about the effects of oestrogen and the interactions between oestrogens and other endocrine factors within the growth plate is important for the development of new treatment strategies in different disorders affecting longitudinal bone growth. As new specific modulators of oestrogen receptors are developed, these could offer more specific ways to modulate longitudinal growth and growth plate fusion.

Androgens↗
PubMed2003

Integrins in growth plate cartilage.

The growth plate is a highly specialized layer of cartilage where chondrocytes proliferate and differentiate in order to bring forth longitudinal bone growth. Interaction of cells with the extracellular matrix significantly influences differentiation and growth. These processes involve integrin as well as nonintegrin cell surface receptors, like annexin V and CD44. In chondrocytes, which are surrounded by abundant matrix, tissue integrity and cell survival depend on well-tuned interactions of cells and ECM. In the field of growth research, besides classical growth stimulating factors acting via endocrine pathways, investigations on local determinants of cell differentiation and survival play an important role. This review describes the role and function of integrins, their occurrence in growth plate cartilage and their possible involvement in differentiation during growth.

Animals↗
PubMed1996

Perinuclear localization of an intracellular binding protein related to the fibroblast growth factor (FGF) receptor 1 is temporally associated with the nuclear trafficking of FGF-2 in proliferating epiphyseal growth plate chondrocytes.

Fibroblast growth factor-2 (FGF-2) is a potent autocrine mitogen for fetal epiphyseal growth plate chondrocytes and exhibits a transient nuclear translocation during G1 of the cell cycle. We have characterized an intracellular binding protein (FGFBP) for FGF-2 that undergoes a juxtanuclear localization coincident with the nuclear translocation of the growth factor. Chondrocytes were isolated from the proliferative zone of the ovine fetal proximal tibial growth plate at 50-130 days gestation by collagenase digestion and were maintained in monolayer at early passage number. Cells were growth restricted by serum starvation for 48 h, and the synchronized culture was restarted into the cell cycle in the presence of 2% FBS. Cells were removed between 4-26 h of incubation, and fractions representing the plasma membrane, cytoplasm, nuclear membrane, and nuclear contents were separated by differential centrifugation. FGFBPs were separated using FGF-2 affinity chromatography. Ligand blot analysis using 125I-labeled FGF-2 showed that a FGFBP of 46-48 kDa (represented by a double band) was present on the nuclear membrane at mid to late G1, and Western blot showed this to be immunologically related to a part of the extracellular domain of the high affinity FGF receptor 1 (FGFR1). Immunocytochemistry with intact cell cultures showed that this protein underwent a juxtanuclear distribution through mid to late G1. Immunoprecipitation was performed to monitor newly synthesized FGFR1 migration throughout the cell cycle. Synchronized cells were cultured in medium containing 35S-labeled methionine/cysteine, and the cellular compartments were separated before immunoprecipitation using an antibody raised against the extracellular domain of FGFR1. Newly synthesized FGFR1-related proteins appeared throughout G1 and migrated multidirectionally within the cell; intact receptor of 125-145 kDa accumulated at the plasma membrane, while both intact receptor and truncated FGFR1 of 46-48 kDa were detected on the nuclear membrane, but not within the nucleus. Cells were incubated with protamine sulfate to prevent the binding of endogenous, cell membrane-associated FGF-2 to high affinity FGFRs and their subsequent internalization. This did not alter the juxtanuclear accumulation of truncated FGFR1 in late G1, suggesting that this was not derived from the plasma membrane. The truncated FGFR1 may mediate the nuclear translocation of FGF-2 during late G1.

Animals↗
PubMed1999

Growth plate cartilage formation and resorption are differentially depressed in growth retarded uremic rats.

To characterize the modifications of growth plate in individuals with growth impairment secondary to chronic renal failure, young rats were made uremic by subtotal nephrectomy (NX) and, after 14 d, their tibial growth plates were studied and compared with those of sham-operated rats fed ad libitum (SAL) or pair-fed with NX (SPF). NX rats were growth retarded and severely uremic. Growth plate height (mean +/- SD) was much greater (P<0.05) in NX (868.4+/-85.4 microm) than SAL (570.1+/-93.5 microm) and SPF (551.9+/-99.7 microm) rats as a result of a higher (P<0.05) hypertrophic zone (661.0+/-89.7 versus 362.8+/-71.6 and 353.0+/-93.9 microm, respectively). The increased size of the growth plate was associated with a greater number of chondrocytes and modifications in their structure, particularly in the hypertrophic zone adjacent to bone. In this zone, chondrocytes of NX animals were significantly (P<0.05) smaller (12080.4+/-1158.3 microm3) and shorter (34.1+/-2.5 microm) than those of SAL (16302.8+/-1483.4 microm3 and 37.8+/-2.0 microm) and SPF (14465.8+/-1521.0 microm3 and 36.3+/-1.8 microm). The interface between the growth plate cartilage and the metaphyseal bone appeared markedly irregular in NX rats. Kinetics of chondrocytes was also modified (P<0.05) in the NX rats, which had lower cell turnover per column per day (5.4+/-0.9), longer duration of hypertrophic phase (89.0+/-15.2 h), and reduced cellular advance velocity (7.4+/-2.2 microm/h) compared with SAL (8.0+/-1.6, 32.1+/-6.7 h, and 11.3+/-2.7 microm/h) and SPF (7.2+/-1.1, 34.8+/-5.1 h, and 10.1+/-2.5 microm/h). Cell proliferation was no different among the three groups. Because the growth plates of SPF and SAL rats were substantially not different, modifications observed in the NX rats cannot be attributed to the nutritional deficit associated with renal failure. These findings indicate that chronic renal failure depresses both the activity of the growth plate cartilage by altering chondrocyte hypertrophy and the replacement of cartilage by bone at the metaphyseal end. The two processes are differentially depressed since cartilage resorption is more severely lowered than cartilage enlargement and this leads to an accumulation of cartilage at the hypertrophic zone.

Animals↗
PubMed2002

The role of the resting zone in growth plate chondrogenesis.

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 removed the proliferative and hypertrophic zones from the rabbit distal ulnar growth plate in vivo, leaving only the resting zone. Within 1 wk, a complete proliferative and hypertrophic zone often regenerated. Next, we manipulated growth plates in vivo 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 seemed to inhibit their hypertrophic differentiation. Our findings suggest that resting zone cartilage makes important contributions to 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 may also produce a morphogen that inhibits terminal differentiation of nearby proliferative zone chondrocytes and thus may be partially responsible for the organization of the growth plate into distinct zones of proliferation and hypertrophy.

Animals↗
PubMed2006

Depletion of resting zone chondrocytes during growth plate senescence.

With age, the growth plate undergoes senescent changes that cause linear bone growth to slow and finally cease. Based on previous indirect evidence, we hypothesized that this senescent decline occurs because growth plate stem-like cells, located in the resting zone, have a finite proliferative capacity that is gradually depleted. Consistent with this hypothesis, we found that the proliferation rate in rabbit resting zone chondrocytes (assessed by continuous 5-bromo-2'-deoxy-uridine labeling) decreases with age, as does the number of resting zone chondrocytes per area of growth plate. Glucocorticoid excess slows growth plate senescence. To explain this effect, we hypothesized that glucocorticoid inhibits resting zone chondrocyte proliferation, thus conserving their proliferative capacity. Consistent with this hypothesis, we found that dexamethasone treatment decreased the proliferation rate of rabbit resting zone chondrocytes and slowed the numerical depletion of these cells. Estrogen is known to accelerate growth plate senescence. However, we found that estradiol cypionate treatment slowed resting zone chondrocyte proliferation. Our findings support the hypotheses that growth plate senescence is caused by qualitative and quantitative depletion of stem-like cells in the resting zone and that growth-inhibiting conditions, such as glucocorticoid excess, slow senescence by slowing resting zone chondrocyte proliferation and slowing the numerical depletion of these cells, thereby conserving the proliferative capacity of the growth plate. We speculate that estrogen might accelerate senescence by a proliferation-independent mechanism, or by increasing the loss of proliferative capacity per cell cycle.

Aging↗
PubMed2005

Cell-cycle control and the cartilage growth plate.

The longitudinal growth of endochondral bones is governed by proliferation and hypertrophic differentiation of growth plate chondrocytes. Numerous growth factors and hormones have been implicated in the regulation of these processes, but the intracellular mechanisms involved remain much less understood. We had suggested a role of cell-cycle genes in the integration of these diverse extracellular signals and their translation into coordinated proliferation and differentiation of chondrocytes. Numerous recent studies have provided support for such a scenario and provide novel insights into the regulation and function of cell-cycle genes in chondrocytes. This review article summarizes recent progress in the field.

Animals↗
PubMed2002

Apoptosis is developmentally regulated in rat growth plate.

Apoptosis occurs in the growth plate during normal and abnormal longitudinal growth. To investigate the role of apoptosis during growth plate maturation, apoptosis and apoptosis-related proteins were studied in rat tibial growth plates at 2, 4, 8, and 11 wk of age. Apoptosis was studied by the terminal deoxynucleotidyl transferase (TdT)-mediated deoxy-UTP nick end-labeling (TUNEL) method, and immunohistochemistry was used to detect p53, caspase-3 and -6, the antiapoptotic proteins Bcl-2 and Bcl-x, and the proapoptotic proteins Bax and Bad. In all age groups studied, most apoptotic chondrocytes were terminal hypertrophic chondrocytes (THPCs) with a significant increase during development. At 2 wk, 0.108 +/- 0.026 THPCs were found to be apoptotic per millimeter of growth plate width; at 4 wk, 0.355 +/- 0.048; at 8 wk, 0.394 +/- 0.043; and at 11 wk, 1.084 +/- 0.069 (p < 0.001; 11 wk vs 2, 4, and 8 wk). THPCs were negative for p53 immunoreactivity at 2 and 4 wk, whereas some THPCs were positive at 8 and 11 wk. Caspase-3 and -6 were found in proliferative and early hypertrophic cells at 2 wk, whereas mature hypertrophic cells and THPCs were negative. At later stages of development, mature hypertrophic cells and THPCs were stained for both caspase-3 and -6. Bcl-2 and Bcl-x were present in proliferative and early hypertrophic cells at 2 wk, whereas at older ages a decrease in staining was observed. At 2 wk of age, Bax and Bad immunoreactivities were localized in proliferative and early hypertrophic cells, whereas at 8 and 11 wk many mature hypertrophic cells and THPCs were immunoreactive for Bax and Bad. Our results show that apoptosis is developmentally regulated in the rat growth plate. In older animals, with decreased growth rate and growth plate height, apoptosis is significantly increased, especially in THPCs.

Animals↗
PubMed2001

Histomorphometric study of growth plate subjected to different mechanical conditions (compression, tension and neutralization): an experimental study in lambs. Mechanical growth plate behavior.

We studied the morphologic effect of low mechanical stresses (compression, tension and neutralization) on the growth cartilage with an external fixator in 18 young lambs. On radiography, we only found more length in the femora subjected to tension (P < 0.05). Bony bridges were not present, nor were there signs of altered vascularization or Ranvier's perichondral ring. Histomorphometrically, in the group subjected to tension, the germinative layer in the femur was higher (P < 0.001) in the bones that had undergone surgery. The proliferative layer was lower in the operated tibia (P < 0.001), and the hypertrophic layer was higher in operated tibias and femora (P < 0.001). In the group subjected to compression, the germinative layer in the femora was higher in the operated bones (P < 0.05); the proliferative layer of the tibia was lower (P < 0.001) and the hypertrophic layer was higher (P < 0.001) in both operated bones. In the neutralization group, the proliferative layer of both operated bones presented lower values (P < 0.001) and the hypertrophic layer was higher (P < 0.001) than that in the control groups.

Animals↗
PubMed2005

Impact of growth plate senescence on catch-up growth and epiphyseal fusion.

In mammals, longitudinal bone growth occurs rapidly in prenatal and early postnatal life, but then slows and eventually ceases. This deceleration, which reflects a decline in chondrocyte proliferation, was previously attributed to a hormonal or other systemic mechanism. However, new evidence suggests that it is due to a local mechanism within the growth plate. In particular, recent findings suggest that growth plate chondrocytes have a finite proliferative capacity that is gradually exhausted, causing growth to slow and finally stop. This concept has provided insight into clinical phenomena including catch-up growth after transient growth inhibition, catch-down growth after transient estrogen exposure, and epiphyseal fusion.

Aging↗