The ability of parathyroid hormone (PTH) to enhance bone formation has recently been exploited in the treatment of osteoporosis. However, the underlying mechanisms are unknown. Osteoblasts, the bone-forming cells, derive from multipotential bone marrow stromal precursors called colony-forming units-fibroblastic (CFU-F) upon culture ex vivo. Adhesion of such stromal precursors to bone is likely to be an early event in the anabolic response of bone to PTH. To test this, we measured the number of CFU-F that could be extracted from murine bone marrow after administration of an anabolic dose of PTH. We found that a very early response is a dramatic reduction, starting within 2 h, in the number of CFU-F that could be extracted from their bone marrow. We then tested whether PTH has the ability to activate adhesion of CFU-F in vitro. For this, bone marrow cells were incubated in PTH for varying times. Non-adherent cells were then removed, and the adherent cells were incubated in PTH-free medium for 14 days to assess, as colony formation, the number of CFU-F that had adhered in the preceding period. We found that incubation in PTH caused a substantial increase in the number of CFU-F that adhered within 24 h. This increase was abrogated by peptidic inhibitors of integrins. The increase did not seem to be mediated through a PTH-induced increase in interleukin-6, since interleukin-6 had no effect on CFU-F numbers when substituted for PTH. Similarly, adhesion was unaffected by incubation of bone marrow cells in dibutyryl cyclic AMP, nor by inhibitors or donors of nitric oxide. However, activation of CFU-F in vitro by PTH was strongly inhibited by indomethacin and mimicked by prostaglandin E(2), and indomethacin reversed the PTH-mediated reduction of CFU-F that could be extracted from mouse bone marrow. These results suggested that PTH rapidly activates adhesion of CFU-F to plastic or bone surfaces. This activation may represent an early event in the anabolic response of bone cells to PTH.
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J Davies and TJ Chambers
I. J. DAVIES and K. J. RYAN
[7-3H]Pregnenolone was incubated with homogenates of adrenal glands from two 100-day-old sheep foetuses. Cortisol and corticosterone were isolated and identified by reverse isotope dilution and recrystallization to constant specific activity. Together these two compounds accounted for 12% and 17% of the substrate with the two tissue preparations. Other C21 and C19 metabolites which were sought were not present in appreciable quantities. Additional incubations were done with the adrenals of lamb foetuses ranging in age from 110 days of gestation to the immediate newborn period. Glucocorticoidogenic capacity similar to that of the 100-day-old foetuses was demonstrated throughout this period and no age-related change was evident. These results demonstrate that the lamb foetal adrenal has a substantial enzymic capacity for glucocorticoid synthesis throughout at least the last third of gestation. In conjunction with the observations of others, these experiments support the hypothesis that during this period of gestation the lamb foetal adrenal is actively synthesizing glucocorticoids in a manner which is similar to the lamb at term and the adult sheep.
D. T. DAVIES and J. COLLINS
After the i.m. injection of 10 μg synthetic LH releasing hormone (LH-RH) into Japanese quail the levels of LH and FSH in plasma rose significantly within 2 min. The increased level of LH declined rapidly but that of FSH was maintained for the duration of the experiment. To determine whether the anterior pituitary gland is primed by LH-RH a double injection schedule was adopted. It would appear that, while endogenous LH-RH may prime the avian pituitary gland slightly, synthetic LH-RH is ineffective.
J. R. G. CHALLIS, I. J. DAVIES, and K. J. RYAN
Pregnant rabbits were treated with indomethacin (8–10 mg/kg/day) or dexamethasone (1·2–1·8 mg/kg/day) during late gestation. The effects of these treatments on the concentrations of progesterone and prostaglandin F (PGF) in the peripheral plasma, and the outcome of gestation were studied. Treatment with indomethacin significantly prolonged the length of gestation (P < 0·01) compared with control, untreated animals. In these treated animals, the plasma progesterone levels declined at a similar time to that in control rabbits but the increase in systemic PGF normally seen during late pregnancy was reduced. Dexamethasone treatment reliably induced premature delivery within 3–6 days. The plasma progesterone concentration fell rapidly during the first 24 h of dexamethasone administration, but in no animal was this associated with a significant increase in the plasma levels of PGF.
These results are consistent with the suggestion that prostaglandins are involved in the normal initiation of parturition in the rabbit. They do not support the hypothesis that the effect of dexamethasone on the length of gestation is mediated through an increase in the production of prostaglandin F.
N. Kyprianou, J. C. Gingell, and P. Davies
Androgen receptors in nuclei from human prostate carcinomas were characterized on the basis of their solubilization by, or resistance to, micrococcal nuclease. By this means, androgen receptors were assigned to three nuclear categories: those associated with nuclease-resistant structures, those associated with chromatin and those apparently uncommitted by association with either of these. Prostate carcinoma nuclei contained high concentrations (57–82% of total nuclear content) of nuclease-resistant androgen receptors. This was a different pattern from that observed previously for benign hypertrophic prostate epithelial nuclei which contained a variable high proportion of uncommitted androgen receptors. The differences could not be attributed to differential losses to cytosol, or to loss of functionality, as determined in vitro. The differences in distribution could reflect different responses of diseased cells to androgens, or the intervention of other factors more relevant to the disease process.
J. Endocr. (1987) 112, 161–169
C. T. M. DAVIES and J. D. FEW
MRC Environmental Physiology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT
(Received 8 April 1976)
Reports on the changes in plasma cortisol level induced by exercise are uncommon, but contradictory. We have previously shown that exercise for 1 h, only leads to a rise in plasma cortisol concentration if the work load exceeds about 60% of the subject's maximal aerobic power (V̄O2, max); that is if his oxygen consumption exceeds 60% of the maximum of which he is capable (Davies & Few, 1973). We have now obtained further evidence of the importance of relative work load (% V̄O2, max) in eliciting an adrenocortical response to exercise, by comparing the changes in plasma cortisol at a given work load under normoxic and hypoxic conditions. The hypoxic condition was breathing 13% oxygen which was expected to reduce V̄O2, max by about 25% (Davies & Sargeant, 1974).
J. J. BROWN, D. L. DAVIES, A. F. LEVER, and J. I. S. ROBERTSON
The present investigation was undertaken to determine the extent to which plasma renin concentration varies during a 24-hr. period of unrestricted activity.
Seven healthy male medical students (aged 20–24) were investigated. Five samples (50 ml.) were taken from an arm vein at 6-hourly intervals from each student at the times indicated in Fig. 1. Since repeated sampling might have produced systematic changes in renin concentration (see Brown, Davies, Lever, Robertson & Verniory, 1965), the experiment was started at different times in individual subjects. In two, the first sample was taken at 10.00 a.m.; in three, at 4.00 p.m.; and in the remaining two at 10.00 p.m. Samples were taken with the subjects in the recumbent position. No attempt was made to limit physical activity or dietary intake during the period of the study. All subjects had been sleeping in the hours before the 4.00 a.m. sample. Plasma renin concentration was
S. J. MAIN, R. V. DAVIES, and B. P. SETCHELL
The acute effects of a specific reduction in androgen feedback to the hypothalamus and pituitary gland have been investigated in male rats by passive immunization against testosterone. An ovine antiserum raised against testosterone which had been conjugated through position 3 to bovine serum albumin was employed.
Negative feedback control by androgens was effectively reduced by administration of the antiserum, as shown by an increase in levels of LH in the circulation. Immunized animals had a high concentration of testosterone in the circulation of which virtually all was tightly bound to antibody.
In normal animals specific increases of serum LH concentration were obtained at all ages using a low dose of antiserum. At higher doses, serum FSH concentration was also increased. The LH response was reduced by anaesthesia and sham-operation. In shamoperated rats given a high dose of antiserum for 3 days the serum concentrations of LH and FSH could not be distinguished from those which followed castration while differences were found in the pituitary contents. It was concluded that testicular androgen provides an important inhibitory feedback control of secretion of FSH as well as that of LH in the adult male rat. Some of the data can best be explained by the action of inhibin as a minor or alternative inhibitor of FSH secretion.
S. J. MAIN, R. V. DAVIES, and B. P. SETCHELL
Spermatogenesis in rats was interrupted by local X-irradiation, heat or ligation of the testicular efferent ducts. A significant and specific rise in the serum level of FSH occurred 5–8 days after ligation of the efferent ducts, reaching twice the value observed in shamoperated controls by 21 days after the operation. After the testes were heated to 43 °C for 30 min, the serum levels of both LH and FSH were raised within 3 days and remained so up to 50 days after treatment. After X-irradiation, no changes in the concentration of FSH were observed in the first 21 days after treatment, but the serum levels of both gonadotrophins were increased at 49 days. By comparing the relative increases in the concentrations of FSH and LH after germ cell damage with those occurring after castration, it was evident that testicular androgens could account for only part of the normal feedback control of FSH secretion; at least one third of the inhibition of FSH secretion appeared to be due to non-androgenic sources, presumably 'inhibin'.
J. S. WOODHEAD, S. JOYCE DAVIES, and D. LISTER
A two-site assay has been developed for bovine PTH. This technique involves reaction of the antigen with two antibody molecules with the purpose of increasing specificity. In practice the hormone was extracted from plasma samples on to plastic tubes coated with antibody specific for PTH (1–34). Uptake was then measured using 125I-labelled antibodies specific for PTH (53–84). In this way a sensitive assay was obtained for PTH (1–84) which did not recognize molecular fragments. This technique was used in conjunction with immunoradiometric assays specific for either NH2-terminal (1–34) or CO2H-terminal (53–84) molecular fragments to study the clearance of infused PTH in the cow. Preliminary results support the hypothesis that the intact molecule is rapidly degraded in the peripheral circulation with the preferential disappearance of an NH 2-terminal fragment. Studies on endogenous secretion during calcium and EDTA infusions indicated that there was little intact hormone present at the times when CO2H-terminal immunoreactivity was readily measured.