Partial prevention of glucocorticoid-induced osteocyte deterioration with osteocrin gene therapy

Glucocorticoid (GC)-induced osteoporosis and subsequent bone fragility are preceded by death and dysfunction at the cellular level. In particular, short-term glucocorticoid excess suppresses osteocyte remodeling of the surrounding bone mineral, causes apoptosis of osteoblasts and osteocytes, and disrupts homeostatic bone remodeling. Preventing apoptosis and preserving osteocyte morphology and function could be effective means of preventing bone loss during glucocorticoid excess. We hypothesized that osteocrin, which preserves osteocyte viability and morphology in other models where osteocyte defects exist, could prevent osteocyte death and dysfunction in a GC excess model. We used a liver-targeted adeno-associated virus (AAV8) to induce osteocrin overexpression in mice one week prior to implantation with prednisolone or placebo pellets. After 28 days, tissues were collected for micro-CT and histological analysis. GC excess caused the expected reduction in cortical bone thickness and osteocyte canalicular length in control AAV8-treated mice, and these effects were blunted in mice overexpressing osteocrin. However, GC-induced changes in cortical porosity, trabecular bone mass, and gene expression were not prevented by osteocrin. While the mechanism of osteocrin's effects on osteocyte morphology warrants further investigation, this study does not support a role for this model of osteocrin supplementation to combat the full skeletal effects of GC excess.

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Structure and function at the cellular level

JAMA ◽

10.1001/jama.198.8.815 ◽

1966 ◽

Vol 198 (8) ◽

pp. 815-825 ◽

Cited By ~ 6

Author(s):

G. E. Palade

Keyword(s):

Cellular Level ◽

Structure And Function ◽

And Function

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Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Cells ◽

10.3390/cells10061552 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1552

Author(s):

Mariona Guitart-Mampel ◽

Pedro Urquiza ◽

Jordana I. Borges ◽

Anastasios Lymperopoulos ◽

Maria E. Solesio

Keyword(s):

Mitochondrial Dysfunction ◽

G Protein ◽

Adrenergic Receptor ◽

Cellular Level ◽

Cardiac Physiology ◽

Failing Heart ◽

Receptor Kinases ◽

And Function ◽

The Impact ◽

G Protein Coupled

The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

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Nuclear Magnetic Resonance Therapy Modulates the miRNA Profile in Human Primary OA Chondrocytes and Antagonizes Inflammation in Tc28/2a Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22115959 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5959

Author(s):

Bibiane Steinecker-Frohnwieser ◽

Birgit Lohberger ◽

Nicole Eck ◽

Anda Mann ◽

Cornelia Kratschmann ◽

...

Keyword(s):

Nuclear Magnetic Resonance ◽

Magnetic Resonance ◽

Protein Level ◽

Cellular Level ◽

Hdac Activity ◽

Hypoxic Conditions ◽

Oa Chondrocytes ◽

Underlying Mechanisms ◽

Induced Changes ◽

Nuclear Magnetic

Nuclear magnetic resonance therapy (NMRT) is discussed as a participant in repair processes regarding cartilage and as an influence in pain signaling. To substantiate the application of NMRT, the underlying mechanisms at the cellular level were studied. In this study microRNA (miR) was extracted from human primary healthy and osteoarthritis (OA) chondrocytes after NMR treatment and was sequenced by the Ion PI Hi-Q™ Sequencing 200 system. In addition, T/C-28a2 chondrocytes grown under hypoxic conditions were studied for IL-1β induced changes in expression on RNA and protein level. HDAC activity an NAD(+)/NADH was measured by luminescence detection. In OA chondrocytes miR-106a, miR-27a, miR-34b, miR-365a and miR-424 were downregulated. This downregulation was reversed by NMRT. miR-365a-5p is known to directly target HDAC and NF-ĸB, and a decrease in HDAC activity by NMRT was detected. NAD+/NADH was reduced by NMR treatment in OA chondrocytes. Under hypoxic conditions NMRT changed the expression profile of HIF1, HIF2, IGF2, MMP3, MMP13, and RUNX1. We conclude that NMRT changes the miR profile and modulates the HDAC and the NAD(+)/NADH signaling in human chondrocytes. These findings underline once more that NMRT counteracts IL-1β induced changes by reducing catabolic effects, thereby decreasing inflammatory mechanisms under OA by changing NF-ĸB signaling.

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Complementary vasoactivity and matrix remodelling in arterial adaptations to altered flow and pressure

Journal of The Royal Society Interface ◽

10.1098/rsif.2008.0254 ◽

2008 ◽

Vol 6 (32) ◽

pp. 293-306 ◽

Cited By ~ 103

Author(s):

A Valentín ◽

L Cardamone ◽

S Baek ◽

J.D Humphrey

Keyword(s):

Smooth Muscle ◽

Continuum Theory ◽

Muscle Contractility ◽

Smooth Muscle Contractility ◽

Rates Of Change ◽

Biomechanical Loading ◽

Smooth Muscle Proliferation ◽

And Function ◽

Diverse Data ◽

Induced Changes

Arteries exhibit a remarkable ability to adapt to sustained alterations in biomechanical loading, probably via mechanisms that are similarly involved in many arterial pathologies and responses to treatment. Of particular note, diverse data suggest that cell and matrix turnover within vasoaltered states enables arteries to adapt to sustained changes in blood flow and pressure. The goal herein is to show explicitly how altered smooth muscle contractility and matrix growth and remodelling work together to adapt the geometry, structure, stiffness and function of a representative basilar artery. Towards this end, we employ a continuum theory of constrained mixtures to model evolving changes in the wall, which depend on both wall shear stress-induced changes in vasoactive molecules (which alter smooth muscle proliferation and synthesis of matrix) and intramural stress-induced changes in growth factors (which alter cell and matrix turnover). Simulations show, for example, that such considerations help explain the different rates of experimentally observed adaptations to increased versus decreased flows as well as differences in rates of change in response to increased flows or pressures.

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The fate and function of glycosphingolipid glucosylceramide

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2003.1266 ◽

2003 ◽

Vol 358 (1433) ◽

pp. 869-873 ◽

Cited By ~ 39

Author(s):

Gerrit van Meer ◽

Jasja Wolthoorn ◽

Sophie Degroote

Keyword(s):

Cellular Differentiation ◽

Membrane Lipids ◽

Early Stage ◽

Cellular Level ◽

Mature Stage ◽

Storage Diseases ◽

Head Groups ◽

Biological Studies ◽

Intracellular Membrane Transport ◽

And Function

In higher eukaryotes, glucosylceramide is the simplest member and precursor of a fascinating class of membrane lipids, the glycosphingolipids. These lipids display an astounding variation in their carbohydrate head groups, suggesting that glycosphingolipids serve specialized functions in recognition processes. It is now realized that they are organized in signalling domains on the cell surface. They are of vital importance as, in their absence, embryonal development is inhibited at an early stage. Remarkably, individual cells can live without glycolipids, perhaps because their survival does not depend on glycosphingolipid–mediated signalling mechanisms. Still, these cells suffer from defects in intracellular membrane transport. Various membrane proteins do not reach their intracellular destination, and, indeed, some intracellular organelles do not properly differentiate to their mature stage. The fact that glycosphingolipids are required for cellular differentiation suggests that there are human diseases resulting from defects in glycosphingolipid synthesis. In addition, the same cellular differentiation processes may be affected by defects in the degradation of glycosphingolipids. At the cellular level, the pathology of glycosphingolipid storage diseases is not completely understood. Cell biological studies on the intracellular fate and function of glycosphingolipids may open new ways to understand and defeat not only lipid storage diseases, but perhaps other diseases that have not been connected to glycosphingolipids so far.

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Sulfate geoengineering: a review of the factors controlling the needed injection of sulfur dioxide

10.5194/acp-2016-985 ◽

2016 ◽

Author(s):

Daniele Visioni ◽

Giovanni Pitari ◽

Valentina Aquila

Keyword(s):

Lower Stratosphere ◽

Effective Means ◽

Climate Engineering ◽

Radiative Effects ◽

Stratospheric Water Vapor ◽

Long Wave ◽

Engineering Technique ◽

Aerosol Effects ◽

Induced Changes ◽

Fine Tune

Abstract. Sulfate geoengineering has been proposed as an affordable and climate-effective means for temporarily offset the warming produced by the increase of well mixed greenhouse gases (WMGHG). This climate engineering technique has been planned for a timeframe of a few decades needed to implement global inter-governmental measures needed to achieve stabilization of the atmospheric content of WMGHGs (CO2 in particular). The direct radiative effects of sulfur injection in the tropical lower stratosphere can be summarized as increasing shortwave scattering with consequent tropospheric cooling and increasing long- wave absorption with stratospheric warming. Indirect radiative effects are related to induced changes in the ozone distribution, stratospheric water vapor abundance, formation and size of upper tropospheric cirrus ice particles and lifetime of longlived species, namely CH4 in connection with OH changes through several photochemical mechanisms. A direct comparison of the net effects of WMGHG increase with direct and indirect effects of sulfate geoengineering may help fine-tune the best amount of sulfate to be injected in an eventual realization of the experiment. However, we need to take into account large uncertainties in the estimate of some of these aerosol effects, such as cirrus ice particle size modifications.

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Impact of diabetes on treatment-induced changes in left ventricular structure and function in hypertensive patients with left ventricular hypertrophy. The LIFE study

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/j.numecd.2008.12.009 ◽

2009 ◽

Vol 19 (5) ◽

pp. 306-312 ◽

Cited By ~ 22

Author(s):

E. Gerdts ◽

P.M. Okin ◽

P. Omvik ◽

K. Wachtell ◽

B. Dahlöf ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Left Ventricular ◽

Structure And Function ◽

Hypertensive Patients ◽

Left Ventricular Structure ◽

Life Study ◽

Ventricular Structure ◽

And Function ◽

Induced Changes

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Proclination-induced changes in the labial cortical bone thickness of lower incisors

Bratislava Medical Journal ◽

10.4149/bll_2019_025 ◽

2019 ◽

Vol 120 (02) ◽

pp. 155-160

Author(s):

D. Filipova ◽

T. Dostalova ◽

V. Filipi ◽

M. Kaminek

Keyword(s):

Cortical Bone ◽

Bone Thickness ◽

Cortical Bone Thickness ◽

Induced Changes ◽

Lower Incisors

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Thallium Induced Changes in Behavioral Patterns: Correlation With Altered Lipid Peroxidation and Lysosomal Enzyme Activity in Brain Regions of Male Rats

Toxicology and Industrial Health ◽

10.1177/074823378500100109 ◽

1985 ◽

Vol 1 (1) ◽

pp. 81-98 ◽

Cited By ~ 15

Author(s):

David R. Brown ◽

Barbara G. Callahan ◽

Mark A. Cleaves ◽

Robert A. Schatz

Keyword(s):

Lipid Peroxidation ◽

Lysosomal Enzyme ◽

Brain Regions ◽

Male Rats ◽

Patterns Of Behavior ◽

Low Levels ◽

Behavioral Sequelae ◽

Human Poisoning ◽

And Function ◽

Induced Changes

The effects of exposures to low levels of heavy metals is a complex and serious problem. Thallium is a metal which produces behavioral sequelae in human poisoning and is potentially hazardous with low level exposures. A test battery is presented which utilizes biochemical and behavioral testing to assess the effects of low levels of thallium on central nervous system chemistry and function in rats. The doses of thallium used (4 and 8 mg/kg) produced no overt signs of behavioral toxicity but did produce dose-related increases in lipid peroxidation and activation of the lysosomal enzyme beta-galactosidase in selected brain regions. At these dose levels, thallium also selectively altered the patterns of behavior. The study suggests that the target regions of thallium in the brain include the cortex, the cerebellum and the brainstem. The dose-response relationships, found for certain pairs of behavioral acts, were correlated with biochemical changes in one or more brain regions.

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