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Search for other papers by M. J. O. FRANCIS in
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SUMMARY
Isolated rat liver, when perfused with medium containing bovine growth homone produced somatomedin-like activity (liver somatomedin).
Liver somatomedin is useful in studies of the hormonal control of the cartilage plate in vitro, since unlike serum it is not contaminated with other hormones or growth factors (apart from growth hormone). Chondrocytes isolated from various regions of the growth cartilage responded differently to liver somatomedin; proliferative chondrocytes, like those isolated from the articular cartilage, showed increased [3H]thymidine uptake in response to liver somatomedin, whereas hypertrophic chondrocytes did not respond. It is suggested that there is a reduction in the response to somatomedin by growth plate chondrocytes as they pass from the proliferative to the hypertrophic state.
Thyroxine, thought to be involved in the processes of hypertrophy and new bone formation, did not directly affect [3H]thymidine uptake by proliferative chondrocytes, but inhibited stimulation of their activity by liver somatomedin.
Measurement of [3H]thymidine uptake by isolated articular chondrocytes may provide a useful assay for both liver and serum somatomedin. The graded response of chondrocytes to increasing concentrations of liver somatomedin paralleled the response to increasing levels of serum somatomedin.
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Plasma somatomedin activity enhanced the incorporation of [3H]thymidine into chondrocytes isolated from human foetal cartilage during weeks 13–21 of gestation. Human growth hormone (0·1–20 μu./ml), human placental lactogen (0·1–5 μg/ml) and insulin (0·25– 10 μu./ml) had no direct effects on the synthesis of DNA in these chondrocytes, although insulin at concentrations of 2·5–100 mu./ml increased [3H]thymidine incorporation by up to 400%.
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The incorporation of [3H]thymidine by rabbit chondrocytes in vitro has been developed as a sensitive assay for plasma somatomedin. A concentration of normal plasma of 2·5% enhanced [3H]thymidine incorporation by 5- to 20-fold compared with basal levels in the absence of plasma. The mean potency of plasma from normal adult men was 0·96 ± 0·1 u./ml (mean ± s.d.) and from acromegalic patients 1·9 ± 0·4 u./ml. The apparent potency of hypopituitary plasma alone increased on heating which suggested the presence of heatlabile inhibitors of somatomedin activity. The potency of heated hypopituitary plasma (0·6 ± 0·09 u./ml) remained significantly lower (P < 0·01) than normal plasma. Human growth hormone (0·1–20 μu./ml), bovine growth hormone (0·5–20 μu./ml), insulin (0·5–5 μu./ml) and glucose (0·3–2 mmol/l) had no direct effect on the incorporation of [3H]thymidine. Chondrocytes which had been previously stored frozen also showed a response to plasma somatomedin.
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Search for other papers by M. J. O. FRANCIS in
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SUMMARY
Plasma somatomedin is the intermediary through which growth hormone (GH) exerts its effects on the growing skeleton. Somatomedin activity may be produced in vitro by perfusion of the liver and kidneys of rats with Waymouth's medium containing GH. The relationship between the activity of plasma somatomedin and somatomedin of hepatic and renal origin has yet to be clarified. Somatomedin from plasma can be separated into active fractions of both high and low molecular weight. Similarly, ultrafiltration of medium containing somatomedin of hepatic origin indicates the existence of two active fractions, one of high molecular weight (greater than 50000) and one of low molecular weight (less than 1000). The latter can be attributed to the release of amino acids, such as serine and glutamine, by the perfused tissue. The high molecular weight fraction is believed to represent GH-dependent somatomedin. Fractions that inhibit production of cartilage matrix are present in liver perfusates as well as in plasma.
These results provide further evidence that the liver is a source of GH-dependent somatomedin in vivo. Furthermore, cartilage growth may be controlled not only by the GH-stimulated release of somatomedin by the liver, but also by its release of acid-labile somatomedin inhibitors.
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Rat prolactin at a concentration of 50 ng/ml perfusion medium stimulated the production of somatomedin-like activity (SLA) from the perfused liver of normal rats. The effect was demonstrable in perfusions performed at 11.00 h in which rat prolactin caused a mean (±s.e.m.) increase in the uptake of [35S]sulphate into rat costal cartilage in vitro of 64 ± 14% in comparison with controls, but at 15.00 h no effect was observed. No effect of rat prolactin on hypophysectomized rat liver was detectable at 11.00 h.
Hypophysectomized and sham-operated rats were given five intravenous injections of 50 μg rat prolactin or a similar volume of hormone solvent at 12 h intervals. Plasma somatomedin activity (SMA) and cartilage metabolism, measured by the uptake of radioactive sulphate and thymidine by costal cartilage in vitro, were similar in hypophysectomized animals given rat prolactin or hormone solvent. Sham-operated rats given rat prolactin showed a significant increase of plasma SMA and cartilage metabolism compared with control animals.
The production of SLA by rat liver in response to rat prolactin may be related to the density of specific hepatic lactogenic receptors, since these are absent or present only in low numbers in hypophysectomized animals.
