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Orthopaedic Proceedings
Vol. 85-B, Issue SUPP_I | Pages 10 - 10
1 Jan 2003
Roach H Mehta G Oreffo R Cooper C Clarke N
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The growth plates of rapidly growing animals have been studied extensively. Nevertheless, several questions remain unanswered, partly because many events happen simultaneously, especially at the vascular front. Terminal chondrocytes are thought to undergo programmed cell death, but the fate of the cell remnants remains unclear. Are the dying cells released into the vascular space and phagocytosed by macrophages, as one would expect for apoptosis? Or are the cells eliminated prior to opening of the lacunae, leaving empty lacunae? Do all terminal chondrocytes die or do some become bone-forming cells? Rodents maintain a growth plate into old age, long after longitudinal growth has ceased. These stationary growth plates have several features not found in the growth plates of rapidly growing animals and closer study of these features may provide answers to the above questions. Femurs and tibiae from 4–16 week-old and 62–80 week-old rats were decalcified, processed into paraffin, and the morphological changes were documented.

Between 4–16 weeks, the heights of the growth plates decreased due to loss of the large hypertrophic chondrocytes, but the various zones were still present. In the aged rats, the growth plates were identifiable as a narrow cartilaginous band with some short columns of inactive cells. The vascular front was irregular, the narrow spicules of primary spongiosa were absent and the much thicker spicules, which are normally seen in secondary spongiosa, directly abutted to the cartilage. Horizontal apposition of bone matrix onto the cartilage edge was frequently present. In addition, the following features were noted. 1) Acellular areas: Nearly all growth plates contained regions of cartilage from which all cells and their lacunae had disappeared. In some cases, these acellular regions stretched from the reserve zone to the vascular front and even persisted as a relatively wide core within the spicules of spongiosa, indicating increased resistance of acellular cartilage to resorption. The absence of cells or cell debris was consistent with an autophagic mode of cell death and subsequent collapse of the lacunae. 2) Remodelling within the growth plate; in some growth plates, large regions of growth plate cartilage had been resorbed and new bone had been laid down in a pattern similar to the remodelling of cortical bone. This suggested that the normal resistance of cartilage to vascular invasion had been lost locally, but was maintained in adjacent non-remodelled regions. 3) Trans-differentiation of chondrocytes to bone-forming cells; extensive new medullary bone formation was noted in the diaphysis of approximately 30% of the aged rats, suggesting that they had received an (unknown) osteogenic stimulus. In these rats, bone matrix was identifiable inside chondrocytic lacunae, and spreading beyond the confines of the lacunae, thus directly replacing growth plate cartilage with bone matrix.

The results suggest that i) chondrocytes are capable of self-elimination, perhaps by a mechanism similar to the autophagic cell death that occurs during insect metamorphosis; ii) resorption of cartilage and vascular invasion requires the presence of the viable chondrocytes; and iii) chondrocytes have the capacity to transdifferentiate to bone-forming cells, but only do so when receiving an increased osteogenic stimulus.


Orthopaedic Proceedings
Vol. 84-B, Issue SUPP_II | Pages 150 - 150
1 Jul 2002
Mehta G Oreffo RO Langley-Evans SC Cooper C Clarke NMP Roach HI
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Cohort studies in humans have suggested that the peak bone mass attained at skeletal maturity may be programmed in utero. To investigate which aspects of bone development might be influenced in utero, we utilised a rat model of maternal protein insufficiency, which has previously been used to demonstrate the fetal origin of adult hypertension. In rodents, a growth plate remains present throughout life, even after longitudinal growth ceases. Generally, the height of the growth plate is related to the rate of bone growth. Fast growing bones have maximal height growth plates, and as bone growth slows down the height decreases until it remains stationary.

The aim of this study was to compare the morphology of long bones in aged rats that had been subjected to protein insufficiency in utero with that of controls. Rat dams were fed either an 18% casein control diet or a 9% casein low protein diet from conception until the end of pregnancy. The offspring were fed a normal diet until death (~72 weeks), when bone density was measured by dual energy X-ray absorptiometry (DEXA) and the tibiae and femurs were processed for histology.

The offspring of rats from the low protein group had a significantly lower bone mass, as assessed by DEXA. The major differences in bone structure were found in the growth plates, which were very irregular without the usual zones of resting, proliferating and hypertrophic chondrocytes. A number of unusual cellular events were noted to have taken place subsequent to cessation of growth, including: a) elimination of all chondrocytes in a number of regions, resulting in vast acellular areas; b) formation of chondroid bone and/or transdifferentiation of chondrocytes to bone-forming cells in other regions; c) partial resorption of those latter regions while the acellular regions were not resorbed; d) ‘horizontal’ apposition of bone against a smooth metaphyseal edge of the growth plate.

To compare the growth plates from the low and high protein groups semi-quantitatively, the degrees of the above features were scored. In addition, the heights of the growth plates were were assessed by two independent measurements. In the low protein group, the height of the growth plate were found to be significantly greater (p< 0.001). Additionally, the growth plates from this group of animals were observed to be more irregular with regards to all the features outlined above.

These findings are consistent with the hypothesis that growth trajectory and bone mass are programmed in early life. The increased height of the growth plate in animals undernourished in utero may reflect the cessation of growth at an earlier age. The increased irregularity of the growth plate in this group of animals may infer an earlier onset of age-related changes within the growth cartilage.