Hexarelin, a growth hormone - Releasing peptide, counteracts bone loss in gonadectomized male rats
ABSTRACT The age-related decline in growth hormone (GH) secretion has been implicated in the pathogenesis of involutional bone loss. Whether restoration of GH secretion might be helpful in maintaining and/or improving bone mass during aging is still unsettled. The aim of the present study was to examine the effects of 30-day treatment with hexarelin (HEXA, 50 microg/kg subcutaneously b.i.d.), a highly effective GH-releasing compound, on bone metabolism and bone mineral density (BMD) in intact and osteopenic gonadectomized (GDX) mature male rats. Serum total alkaline phosphatase (ALP, bone formation marker) and bone resorption markers (lysylpyridinoline, LP and hydroxylysylpyridinoline, HP) were measured before and 7, 14 and 30 days after treatment. BMD was measured by dual-energy X-ray absorptiometry at lumbar vertebrae, femoral metaphysis and diaphysis before and at the end of the experiment. In intact rats, HEXA significantly (P<0.05) decreased LP (-36.3%) and HP (-22.8%) excretion at day 7, whereas it did not change serum ALP activity and BMDs. In GDX rats, HEXA completely prevented the significant (P<0. 01) increase in urinary excretion of both LP (+143.8%) and HP (+119. 4%), the early decrease in ALP activity (-26.5%) and the significant (P<0.05) decrease in BMDs in the femoral metaphysis (-7.9%) and lumbar vertebrae (-6.8%) caused by androgen deficiency. The bone-protective effects of HEXA could be attributed, at least in part, to its GH-releasing activity since chronic-treated rats maintained the GH response to an acute challenge with HEXA. The evidence that HEXA, unlike GH, inhibits bone resorption indicates that other mechanisms contribute to the bone sparing effect of HEXA.
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- "In vivo, ghrelin may have an indirect effect on bone through its stimulation of GH release. However, the GHS-R1a agonist hexarelin inhibits markers of bone resorption in the rat, an effect not observed with GH treatment (Sibilia et al. 1999). This suggests that GH secretagogues may have GH-independent effects on bone in rodents. "
ABSTRACT: Recent studies demonstrate widespread expression of ghrelin among tissues and have uncovered its pleiotropic nature. We have examined gene expression of ghrelin and its two receptor splice variants, growth hormone secretagogue receptors (GHS-R) 1a and 1b, in human bone biopsies and in the human pre-osteoblastic SV-HFO cell line during differentiation. Additionally, we examined proliferative effects of ghrelin and unacylated ghrelin (UAG) in differentiating and non-differentiating cells. We detected GHS-R1b mRNA in human bone and osteoblasts but not ghrelin's cognate receptor GHS-R1a, using two different real-time PCR assays and both total RNA and mRNA. In osteoblasts GHS-R1b mRNA expression remained low during the first 14 days of culture, but increased 300% in differentiating cells by day 21. Both human bone biopsies and osteoblasts expressed ghrelin mRNA, and osteoblasts were found to secrete ghrelin. Overall, ghrelin gene expression was greater in differentiating than non-differentiating osteoblasts, but was not increased during culture in either group. Ghrelin and UAG induced thymidine uptake dose-dependently, peaking at 1 and 10 nM respectively, at day 6 of culture in both non-differentiating and differentiating osteoblasts. The proliferative response to ghrelin and UAG declined with culture time and state of differentiation. The proliferative effects of ghrelin and UAG were suppressed by inhibitors of extracellular-signal-regulated kinase (ERK) and phosphoinositide-3 kinase, and both peptides rapidly induced ERK phosphorylation. Overall, our data suggest new roles for ghrelin and UAG in modulating human osteoblast proliferation via a novel signal transduction pathway.Journal of Endocrinology 02/2006; 188(1):37-47. DOI:10.1677/joe.1.06404 · 3.59 Impact Factor
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ABSTRACT: Moisture disposal and thermal behaviour (shoe climate) over a number of hours is an important factor in shoe comfort, besides the fit of the shoes and energy (absorption). In most of shoe-testing laboratories these properties are frequently measured on materials, like leather linings and upper- or in-soles. Data for these materials can give an indication of the performance of the shoe, although differences can occur dependent on the shoe construction and the production methods used. At TNO, a test-method, the WSCR-method (Whole Shoe Comfort Rating), is set up where both the water vapour transport and thermal characteristics of complete shoes can be measured with the aid of an artificial foot. The method uses a flexible sock that is impermeable to water, but permeable to water vapour. This sock is placed into the shoe specimen, which is filled with water at a controlled temperature. The whole set-up is placed upon a balance (connected to a computer), in a laboratory (20°C and 65% relative humidity) or in a climatic chamber or box. The air speed is maintained at approximately 1 m/s. The Water Vapour Absorption, Water Vapour Permeability and Water Vapour Transport (WVT) are calculated from the measurements, as well as the average heat conductivity of the whole shoe.Five different trekking shoes were compared for (thermal) comfort. The results show that the shoe with the highest WVT-value have a 35% higher value than the shoe with the lowest value. For heat resistance, the same type of shoe had a 30% higher value than the lowest. The heat resistance and WVT values showed a significant negative correlation (−0.97; p<0.01). It can be concluded that the trekking shoes have a worse performance with regard to comfort compared to the other shoes, but in terms of functionality the trekking shoes were better than the other shoes. The present study shows the importance of different comfort aspects (e.g. climate, fit, shock absorption) and should lead to a whole shoe comfort model that will help in evaluating the comfort of shoes in an objective manner.
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ABSTRACT: New data support a role for growth hormone secretagogue receptor agonists as rejuvenating agents. Two enzymes critical for the formation of beta-amyloid plaques in Alzheimer's disease have been identified. Estrogen receptor beta continues to emerge as a potential drug target. The orphan nuclear receptor Nurr1 appears to be a target for treatment of Parkinson's disease, and propargylamines are emerging as inhibitors of oxidative damage in neurons.Current Opinion in Chemical Biology 09/2000; 4(4):371-6. DOI:10.1016/S1367-5931(00)00104-6 · 7.65 Impact Factor