Chronic inflammatory diseases of almost any cause are associated with bone loss. Bone loss is due to direct effects of inflammation, poor nutrition, reduced lean body mass, immobility and the effects of treatments, especially glucocorticoids. These mechanisms are complex and interrelated but are ultimately mediated through effects on the bone remodelling cycle. Inflammatory disease can increase bone resorption, decrease bone formation but most commonly impacts on both of these processes resulting in an uncoupling of bone formation from resorption in favour of excess resorption. This review will illustrate these interactions between inflammation and bone metabolism and discuss how these are, and might be, manipulated as therapies for inflammation related bone loss.
R Hardy and M S Cooper
K. J. COOPER, C. P. FAWCETT and S. M. McCANN
Results of experiments using steroid injections or implants have indicated that pituitary gonadotrophin secretion is not only modified by a change in perfusion rate of the releasing factors (RF) of luteinizing hormone (LH) and follicle-stimulating hormone, but that steroid feedback directly at the pituitary level may be involved in the cyclic regulation of gonadotrophin secretion (Ramirez, Abrams & McCann, 1964; Harris & Campbell, 1966; Arimura & Schally, 1971). Consequently, it has been suggested that pituitary responsiveness to LH-RF might change during the oestrous cycle as a result of variation in steroid secretion (Antunes-Rodrigues, Dhariwal & McCann, 1966). This experiment investigates this possibility.
Female Sprague—Dawley rats weighing 220–250 g and maintained under a lighting régime of 14 h light: 10 h darkness at a temperature of 21 ± 2 °C were used. Only animals showing at least two consecutive 4-day oestrous cycles were studied. LH-RF-evoked stimulation of LH release was examined
A. D. CARE, L. L. ANDERSON, C. W. COOPER, S. L. OXENREIDER and M. PHILLIPPO
The surgically isolated thyroid gland in the pig has been shown to secrete thyrocalcitonin (TC) when perfused with an artificial medium, hypercalcaemic with respect to ionized calcium concentration (Care & Gitelman, 1968). Therefore, hypophysial hormones must not be essential for the release of at least some TC stimulated by hypercalcaemia. The present work was designed to evaluate quantitatively the effect of previous hypophysectomy on the rate of secretion of TC in response to a given degree of hypercalcaemia.
In preliminary experiments, a pair of litter-mate male piglets, 19 days old, was selected and one was hypophysectomized by an adaptation of the method of Liggins, Kennedy & Holm (1967). At autopsy, hypophysectomy was confirmed by visual examination of the sella turcica. Nine days after operation, the thyroid was isolated in situ and perfused with hypercalcaemic blood (6·7 m-equiv.Ca/1.) for 2 hr. according to the method of Care (1965). The thyroid of
R. M. Sharpe, I. A. Swanston, I. Cooper, C. G. Tsonis and A. S. McNeilly
Immunoreactive inhibin was measured in testicular interstitial fluid (IF) from rats during sexual maturation or after impairment of spermatogenesis induced by ethane dimethanesulphonate (EDS), unilateral cryptorchidism or local heating (43 °C, 30 min) of the testes, to ascertain its usefulness as a marker of changing Sertoli cell function. Cultures of isolated seminiferous tubules were also studied. Inhibin was measured by a radioimmunoassay directed towards the first 26 amino acids of the N-terminus of the α-subunit, and the results confirmed for selected pools of IF by in-vitro bioassay using dispersed ovine pituitary cells.
During puberty, IF levels of immunoactive inhibin fell by more than 90% (P<0·001) between 30 and 60 days of age, a decrease paralleled by the levels of androgen-binding protein (ABP), another Sertoli cell product secreted into IF. These changes also paralleled, but preceded, the fall (60%; P<0·001) in serum levels of FSH between 40 and 70 days, while the serum and IF levels of testosterone increased more than two-fold over this period. When adult rats were injected with EDS to destroy the Leydig cells, testosterone levels in IF and serum were undetectable at 3 and 7 days after treatment, were just detectable at 14 days and thereafter returned slowly towards normal by 42 days. The initial androgen withdrawal following EDS treatment caused a progressive reduction in testicular weight up to 21 days and this was accompanied by a significant increase in the serum levels of FSH and a two- to threefold increase in the IF levels of immunoactive inhibin (and also of ABP). Serum FSH and IF levels of immunoactive inhibin returned to within the normal range by 42 days when testosterone levels had normalized. In contrast, in two other experimental situations in which a marked decrease in testicular weight coupled with an increase in IF levels of ABP occurs, different results for the IF levels of immunoactive inhibin were obtained. Thus, in rats exposed to local heating of the testes, IF levels of immunoactive inhibin remained unchanged from control values at 21–40 days after treatment, a finding confirmed by bioassay results. In rats made unilaterally cryptorchid for 10 months, levels of immunoactive inhibin in IF were reduced by 60% (P<0·01) in the abdominal compared with the contralateral scrotal testis.
These results suggest that (1) IF levels of immunoactive inhibin do not always change in parallel to the levels of ABP and may be a useful marker of changing Sertoli cell function, and (2) in at least two situations (puberty and after EDS treatment), there may be a positive relationship between the serum levels of FSH and the IF levels of immunoactive inhibin. This positive relationship was confirmed by in-vitro findings in which FSH and dibutyryl cyclic AMP (but not testosterone) were shown to stimulate immunoactive inhibin production by isolated rat seminiferous tubules during culture for 2–6 days.
J. Endocr. (1988) 119, 315–326
Craig L Doig, Jamila Bashir, Agnieszka E Zielinska, Mark S Cooper, Paul M Stewart and Gareth G Lavery
The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can amplify tissue GC exposure. Elevated TNFα is a common feature in a range of inflammatory disorders and is detrimental to muscle function in diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease. We have previously demonstrated that 11β-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNFα treatment and suggested that this is an autoregulatory anti-inflammatory mechanism. This upregulation was mediated by the P2 promoter of the Hsd11b1 gene and was dependent on the NF-κB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11b1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNFα treatment, NF-κB p65 was translocated to the nucleus. However, ChIP analysis demonstrated that the direct binding was seen at position −218 to −245 bp of the Hsd11b1 gene's P1 promoter but not at the P2 promoter. These studies demonstrate the existence of differential regulation of 11β-HSD1 expression in muscle cells through TNFα/p65 signalling and the P1 promoter, further enhancing our understanding of the role of 11β-HSD1 in the context of inflammatory disease.