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Timing is a critical factor in neuroendocrinology. Despite this, the temporal aspects of glucocorticoid signaling in the regulation of in vivo targets have been largely overlooked. Here, we present data showing that plasma glucocorticoid levels differ greatly from the constant signal predominantly used in cell culture experiments. Using an automated blood sampling system, we found that under basal conditions in nonstressed rats, corticosterone release occurs in discrete pulses of various amplitudes dependent on the circadian cycle. This basal pattern changes to a prolonged elevated nonpulsatile release in response to stressful stimuli. We have been able to recapitulate these different patterns of corticosterone presentation (short pulse vs. prolonged elevation) in adrenalectomized rats, and show that each pattern results in differential activation of hippocampal glucocorticoid and mineralocorticoid receptors. Finally, we provide evidence for a rapid proteasome-dependent clearance of activated glucocorticoid receptors, but not mineralocorticoid receptors, as a novel mechanism to allow dynamic interaction with rapidly changing physiological and environmental conditions.

Atkinson HC, Wood SA, Castrique ES, Kershaw YM, Wiles CC, Lightman SL. Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor. Am J Physiol Endocrinol Metab 294: E1011-E1022, 2008. First published March 18, 2008 doi:10.1152/ajpendo.00721.2007.-The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal (HPA) axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every 5 min from conscious rats at the diurnal peak, using an automated blood sampling system, and assayed for corticosterone. Feedback inhibition by rapidly increasing concentrations of ligand was achieved with an intravenous bolus of exogenous corticosteroid. This resulted in a significant reduction in plasma corticosterone concentrations within 23 min of the aldosterone bolus and 28 min of methylprednisolone. Evaluation of the pulsatile secretion of corticosterone revealed that the secretory event in progress at the time of administration of exogenous steroid was unaffected, whereas the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (1 secretory event only), whereas that of methylprednisolone persisted for 4 -5 h. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 min and corticosterone within 20 min. The inhibitory effect of aldosterone was unaffected by pretreatment with the glucocorticoid receptor antagonist RU-38486 but blocked by the canrenoate. These data imply an important role for the mineralocorticoid receptor in fast feedback of basal HPA activity and suggest that mineralocorticoids can dynamically regulate basal corticosterone concentrations during the diurnal peak, a time of day when there is already a high level of occupancy of the cytoplasmic mineralocorticoid receptor. corticosterone; basal; pulsatility; ultradian; canrenoate; RU-38486; mifepristone CORTICOSTEROID FEEDBACK on the hypothalamic-pituitary-adrenal (HPA) axis is primarily mediated via the genomic actions of the transcription factors mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) (27). MR is understood to regulate tonic HPA activity, whereas GR mediates the recovery from a stress response (13). In addition to the classic genomic mechanisms of feedback, there is also evidence for ratesensitive steroid feedback in a nongenomic time frame that was first identified in rodents in 1969 (10) and has subsequently been confirmed in humans (11). Despite numerous studies, there is as yet no clear site or mechanism for the fast feedback despite investigations at pituitary, hypothalamus, and other brain centers (1,12,16,45,49). There is, however, recent electrophysiological evidence in vitro that confirms a rapid inhibitory nongenomic action of corticosterone in hippocampal slices in mice that is depen...

ObjectivesBisphosphonates (BP) are the first-line treatment for preventing fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate is associated with over-suppression of remodelling and accumulation of microcracks. While dual-energy X-ray absorptiometry (DXA) scanning may show a gain in bone density, the impact of this class of drug on mechanical properties remains unclear. We therefore sought to quantify the mechanical strength of bone treated with BP (oral alendronate), and correlate data with the microarchitecture and density of microcracks in comparison with untreated controls.MethodsTrabecular bone from hip fracture patients treated with BP (n = 10) was compared with naïve fractured (n = 14) and non-fractured controls (n = 6). Trabecular cores were synchrotron scanned and micro-CT scanned for microstructural analysis, including quantification of bone volume fraction, microarchitecture and microcracks. The specimens were then mechanically tested in compression.ResultsBP bone was 28% lower in strength than untreated hip fracture bone, and 48% lower in strength than non-fractured control bone (4.6 MPa vs 6.4 MPa vs 8.9 MPa). BP-treated bone had 24% more microcracks than naïve fractured bone and 51% more than non-fractured control (8.12/cm2 vs 6.55/cm2 vs 5.25/cm2). BP and naïve fracture bone exhibited similar trabecular microarchitecture, with significantly lower bone volume fraction and connectivity than non-fractured controls.ConclusionBP therapy had no detectable mechanical benefit in the specimens examined. Instead, its use was associated with substantially reduced bone strength. This low strength may be due to the greater accumulation of microcracks and a lack of any discernible improvement in bone volume or microarchitecture. This preliminary study suggests that the clinical impact of BP-induced microcrack accumulation may be significant.Cite this article: A. Jin, J. Cobb, U. Hansen, R. Bhattacharya, C. Reinhard, N. Vo, R. Atwood, J. Li, A. Karunaratne, C. Wiles, R. Abel. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res 2017;6:602–609. DOI: 10.1302/2046-3758.610.BJR-2016-0321.R1.