Cell kinetics and the control of bone growth.
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Biomedical subjects
Publications and source records attributed to N F Kember.
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The growth behaviour of chondrocytic clones in the cell columns of the proximal tibial growth plates of young rabbits was modelled in computer simulations. Simulations were performed, modelling either clones in large groups of columns or clones in one single column. The former were based on morphological data and measurements of cell columns from an earlier study while the latter utilised previous findings of cellular kinetics in rabbit growth plates. Simulation results that resembled most closely the actual observations on rabbit growth plates were those in which a distribution of values was assumed both for clone length (ranging from 1000 to 2000 microns) and for the lengths of the discontinuities between clones. When the assumption was made in the models that the disappearing (metaphyseal) end of an 'old' clone moved more rapidly than the developing (epiphyseal) end of a 'new' clone, replacing the former, the length of the discontinuity between these two clones increased with time. This assumption, which could be modelled in the simulations of clones in a single column based on cell growth behaviour, was found to provide an explanation for an earlier finding that there are more short columns at the epiphyseal side than at the metaphyseal side of a growth plate.
New data on the cell kinetics of the cartilage growth plates in the chicken, budgerigar and rhea derived from studies with tritiated thymidine labelling are given. Quantitative histological measurements on growth plates from leg bones (tibiotarsus, tarsometatarsus and a phalangeal bone) in a further five species of birds are presented. Counts of flat cells and measurements of the average diameter of hypertrophic cells were made for each growth plate. These data are compared with values for the overall growth rates of the bones. The variation in sizes of hypertrophic cells was small and it is concluded that the largest factor in determining the growth rate of an avian bone is the size of the zone of flat cells.
The theory that links cell division in epiphyseal cartilage plates to overall growth of long bones has been extended from linear growth systems to those in which proliferating and hypertrophied cells are not arranged in columns. Consideration has also been given to the analysis of non-parallel growth systems. The theory is illustrated by examples from the growth of chicken bones.
An in vitro technique has been used to label dividing cells in the growth plates of human bones with tritiated thymidine. The patterns of labelling in autoradiographs of human plates are described and values given for the labelling index, the number of cells in the proliferation zones and the heights of hypertrophied cells. In two of the four subjects no labelled cells were found in the growth plates and possible causes for these failures are discussed. In vitro labelling data on five porcine growth plates are also presented for comparison with the human data. In both structure and cell kinetics the epiphyseal cartilage plate in the pig is intermediate between the human and rodent plates.
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Mice homozygous for the recessive gene achondroplasia (cn) aged 16 and 17 days and some homozygotes aged 22-34 days have disruptions in the growth of the proximal tibial growth plate which are due solely to reduced hypertrophic cell height. A second class of homozygote, distinguishable at 22 days, has a greater disruption due to much reduced hypertrophic cell height, reduced labelling index and reduction of the number of cells in the effective proliferative zone.
The gene for spondylo-metaphyseal chondrodysplasia (smc) in the mouse disrupts the formation of growth plate cartilage. No cartilage columns are found in the head of the tibia and secondary centres of ossification appear very late. The number of cells labelled with tritiated thymidine is sharply reduced at 16, 18 and 21 days of age but hypertrophic cell height is normal. Cells taking up label are found scattered throughout the large cartilaginous epiphyses.
The proximal growth plates of the tibiae in normal and stumpy mice aged 10-41 days were studied. Autoradiographic studies using tritiated thymidine enabled the size of the proliferating cell population and the labelling indices of the growth plates to be determined. Hypertrophic cell heights were also measured. From these data the overall growth rates for the proximal growth plate of the tibia in normal and stumpy mice were calculated. It was found that the major factor responsible for the reduced growth rate in stumpy up to 21 days was the small hypertrophic cell height, while cell proliferation zone size and labelling indices were of minor importance. Histological observations also revealed a lack of organised endochondral ossification, which worsens with age.
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The measurement of the physical parameters of a high-energy proton beam, using a range of liquid and solid tissue substitutes, is described. The system, the detectors used and the experimental verification of the tissue equivalence of the new tissue substitutes is presented. The measurements with the scattered but uncollimated proton beam in muscle- and brain-equivalent liquids and in water are compared to similar data obtained from the scattered but collimated beam. The effect of lung, fat and bone on the dose distributions in composite phantoms is also investigated and the necessary corrections established. A simulated patient treatment indicated that the Bragg peak can be positioned with an error not exceeding +/- 0.5 mm.
The DC II mouse chondrosarcoma is a potentially valuable radiobiological tumour system since it has been observed to recover from radiation injury by regrowth from clones that may be counted in histological sections. Unfortunately, the normal growth of this tumour following s.c. implantation in the thigh is irregular both in the time before growth becomes evident and in the rate of growth. The response to radiation is also unreliable since tumours irradiated with the same dose (e.g. 30 Gy) show a range of responses from shrinkage to no detectable change in growth rate. The delay in normal growth can be attributed largely to delays in vascularization while changes in growth rate may be explained by differences in tumour architecture. Radiation response may depend on variations in hypoxic fraction and in relative cellularity. Tumours having the same external dimensions may differ by a factor of 80 in the numbers of tumour cells they contain. This chondrosarcoma may prove a closer model to some human tumours than many transplantable tumours that display regular growth patterns.
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The cell kinetics of the cartilage growth plate are outlined and discussed in terms of the probable levels of control on the system. Possible mechanisms of growth control at the cellular level are examined for (i) the rate of cell division in the proliferation zone, (ii) the command to differentiate that limits the size of the proliferation zone and (iii) the ageing process in the cartilage plate. The evidence of cell kinetics does not point unequivocally to any particular mechanism.
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A study is presented of the histological structure and growth rate of the growth plate at the distal end of the femur in normal children. From a comparison of quantitative histological information from post-mortem specimens with measurements on serial radiographs it is estimated that the distal growth plate contributes about 66% of the total longitudinal growth of the bone. The marked differences between rodent and man indicate that caution is required in extrapolating data from these animals to man.
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