Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice

Androgens play a key role in skeletal growth and maintenance in males and can mediate their actions, at least in part, via the androgen receptor (AR) in osteoblasts. To investigate the mechanisms by which androgens exert their effects via the AR in mineralizing osteoblasts and osteocytes, we identified gene targets/pathways regulated by the AR using targeted gene expression and microarray approaches on bone isolated from mice in which the AR is specifically deleted in mineralizing osteoblasts and osteocytes (mOBL-ARKOs). Gene ontology mining indicated a number of biological processes to be affected in the bones of mOBL-ARKOs including skeletal and muscular system development and carbohydrate metabolism. All genes identified to have altered expression in the bones of mOBL-ARKOs were confirmed by Q-PCR for their androgen responsiveness in an androgen deprivation and replacement mouse model. The osteoblast genes Col1a1 and Bglap and the osteoclast genes Ctsk and RANKL (Tnfs11) were upregulated in the bones of mOBL-ARKOs, consistent with the increased matrix synthesis, mineralization, and bone resorption observed previously in these mice. Of significant interest, we identified genes involved in carbohydrate metabolism (adiponectin and Dpp4) and in growth and development (GH, Tgfb (Tgfb2), Wnt4) as potential targets of androgen action via the AR in mineralizing osteoblasts.

Download Full-text

State of neuromuscular transmission in vibration disease, according to electroneuromyographic test

Vestnik nevrologii, psihiatrii i nejrohirurgii (Bulletin of Neurology, Psychiatry and Neurosurgery) ◽

10.33920/med-01-2007-05 ◽

2020 ◽

pp. 55-68

Author(s):

Sergey Babanov

Keyword(s):

Neuromuscular Transmission ◽

System Development ◽

Disease Type ◽

Functional Mobility ◽

Sensorimotor System ◽

Muscular System ◽

Vibration Disease ◽

Regional Center ◽

Occupational Disorders ◽

Sensory Polyneuropathy

The article covers the particular features of the neuro-muscular system in vibration disease of various types and severity by electroneuromyographical tests at the Department of Occupational Disorders, Regional Center for Occupational Disorders, Samara Medical and Sanitary Unit № 5 of the Kirov Region (State Budgetary Healthcare Institution of the Samara Region). Changes in excitability and functional mobility of the sensorimotor system, development of vegetative-sensory polyneuropathy depending on the vibration disease type, severity, and the length of exposure to vibration at work are found in vibration disease patients.

Download Full-text

Study of androgen action in bone by analysis of androgen-receptor deficient mice

Journal of Bone and Mineral Metabolism ◽

10.1007/s007740200047 ◽

2002 ◽

Vol 20 (6) ◽

pp. 326-330 ◽

Cited By ~ 14

Author(s):

Takashi Sato ◽

Hirotaka Kawano ◽

Shigeaki Kato

Keyword(s):

Androgen Receptor ◽

Androgen Action ◽

Deficient Mice

Download Full-text

Regional Expression of Androgen Receptor Coregulators and Androgen Action in the Mouse Epididymis

Journal of Andrology ◽

10.2164/jandrol.110.012914 ◽

2011 ◽

Vol 32 (6) ◽

pp. 711-717 ◽

Cited By ~ 11

Author(s):

P. Sipila ◽

A. Krutskikh ◽

D. A. Pujianto ◽

M. Poutanen ◽

I. Huhtaniemi

Keyword(s):

Androgen Receptor ◽

Androgen Action ◽

Mouse Epididymis

Download Full-text

Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells

Developmental Neuroscience ◽

10.1159/000453258 ◽

2016 ◽

Vol 38 (5) ◽

pp. 375-383 ◽

Cited By ~ 13

Author(s):

Jessica J. DeWitt ◽

Patrick M. Hecht ◽

Nicole Grepo ◽

Brent Wilkinson ◽

Oleg V. Evgrafov ◽

...

Keyword(s):

Immune Response ◽

Chromatin Remodeling ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Multiple Comparisons ◽

Neural Progenitor ◽

Autism Spectrum ◽

Biological Processes ◽

Altered Expression ◽

Genome Wide

The long noncoding RNA MSNP1AS (moesin pseudogene 1, antisense) is a functional element that was previously associated with autism spectrum disorder (ASD) with genome-wide significance. Expression of MSNP1AS was increased 12-fold in the cerebral cortex of individuals with ASD and 22-fold in individuals with a genome-wide significantly associated ASD genetic marker on chromosome 5p14.1. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of moesin protein, which is involved in neuronal process stability. In this study, we hypothesize that MSNP1AS knockdown impacts global transcriptome levels. We transfected the human neural progenitor cell line SK- N-SH with constructs that caused a 50% suppression of MSNP1AS expression. After 24 h, cells were harvested for total RNA isolation. Strand-specific RNA sequencing analysis indicated altered expression of 1,352 genes, including altered expression of 318 genes following correction for multiple comparisons. Expression of the OAS2 gene was increased >150-fold, a result that was validated by quantitative PCR. Gene ontology analysis of the 318 genes with altered expression following correction for multiple comparisons indicated that upregulated genes were significantly enriched for genes involved in immune response, and downregulated genes were significantly enriched for genes involved in chromatin remodeling. These data indicate multiple transcriptional and translational functions of MSNP1AS that impact ASD-relevant biological processes. Chromatin remodeling and immune response are biological processes implicated by genes with rare mutations associated with ASD. Our data suggest that the functional elements implicated by association of common genetic variants impact the same biological processes, suggesting a possible shared common molecular pathway of ASD.

Download Full-text

New Observation on Androgen Action: Androgen Receptor Stabilization and Antisteroid Effects of LHRH Agonists

Advances in Experimental Medicine and Biology - Hormones and Cancer ◽

10.1007/978-1-4615-7192-6_19 ◽

1982 ◽

pp. 325-336 ◽

Cited By ~ 2

Author(s):

W. Wright ◽

K. Chan ◽

K. Sundaram ◽

C. W. Bardin

Keyword(s):

Androgen Receptor ◽

Lhrh Agonists ◽

Androgen Action

Download Full-text

The role of the androgen receptor as a driver and mitigator of cellular stress

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0057 ◽

2020 ◽

Vol 65 (2) ◽

pp. R19-R33

Author(s):

Dimitrios Doultsinos ◽

Ian Mills

Keyword(s):

Prostate Cancer ◽

Protein Synthesis ◽

Androgen Receptor ◽

Cancer Progression ◽

Prostate Gland ◽

Specific Antigen ◽

Nuclear Hormone Receptor ◽

Biological Processes ◽

Normal Prostate ◽

Mtor Activity

Prostate cancer is a high-incidence male cancer, which is dependent on the activity of a nuclear hormone receptor, the androgen receptor (AR). Since the AR is required for both normal prostate gland development and for prostate cancer progression, it is possible that prostate cancer evolves from perturbations in AR-dependent biological processes that sustain specialist glandular functions. The archetypal example of course is the use of prostate specific antigen (PSA), an organ-type specific component of the normal prostate secretome, as a biomarker of prostate cancer. Furthermore, localised prostate cancer is characterised by a low proliferative index and a heterogenous array of somatic mutations aligned to a multifocal disease pattern. We and others have identified a number of biological processes that are AR dependent and represent aberrations in significant glandular processes. Glands are characterised by high rates of metabolic activity including protein synthesis supported by co-dependent processes such as glycosylation, organelle biogenesis and vesicle trafficking. Impairments in anabolic metabolism and in protein folding/processing will inevitably impose proteotoxic and oxidative stress on glandular cells and, in particular, luminal epithelial cells for which secretion is their primary function. As cancer develops there is also significant metabolic dysregulation including impaired negative feedback effects on glycolytic and anabolic activity under conditions of hypoxia and heightened protein synthesis due to dysregulated PI 3-kinase/mTOR activity. In this review we will focus on the components of the AR regulome that support cancer development as well as glandular functions focussing on the unfolded protein response and on regulators of mTOR activity.

Download Full-text

Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0848 ◽

2009 ◽

Vol 94 (1) ◽

pp. 277-284 ◽

Cited By ~ 92

Author(s):

Ilpo T. Huhtaniemi ◽

Stephen R. Pye ◽

Kate L. Limer ◽

Wendy Thomson ◽

Terence W. O'Neill ◽

...

Keyword(s):

Androgen Receptor ◽

Cag Repeats ◽

Androgen Action

Download Full-text

Bioreactor-Controlled Physoxia Regulates TGF-β Signaling to Alter Extracellular Matrix Synthesis by Human Chondrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms20071715 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1715 ◽

Cited By ~ 3

Author(s):

Holger Jahr ◽

Seval Gunes ◽

Annika-Ricarda Kuhn ◽

Sven Nebelung ◽

Thomas Pufe

Keyword(s):

Extracellular Matrix ◽

Oxygen Tension ◽

Molecular Mechanisms ◽

Matrix Metalloproteases ◽

Human Chondrocytes ◽

Marker Genes ◽

Matrix Synthesis ◽

Altered Expression ◽

Positive Effects ◽

Marker Expression

Culturing articular chondrocytes under physiological oxygen tension exerts positive effects on their extracellular matrix synthesis. The underlying molecular mechanisms which enhance the chondrocytic phenotype are, however, still insufficiently elucidated. The TGF-β superfamily of growth factors, and the prototypic TGF-β isoforms in particular, are crucial in maintaining matrix homeostasis of these cells. We employed a feedback-controlled table-top bioreactor to investigate the role of TGF-β in microtissues of human chondrocytes over a wider range of physiological oxygen tensions (i.e., physoxia). We compared 1%, 2.5%, and 5% of partial oxygen pressure (pO2) to the ‘normoxic’ 20%. We confirmed physoxic conditions through the induction of marker genes (PHD3, VEGF) and oxygen tension-dependent chondrocytic markers (SOX9, COL2A1). We identified 2.5% pO2 as an oxygen tension optimally improving chondrocytic marker expression (ACAN, COL2A1), while suppressing de-differentiation markers (COL1A1, COL3A1). Expression of TGF-β isoform 2 (TGFB2) was, relatively, most responsive to 2.5% pO2, while all three isoforms were induced by physoxia. We found TGF-β receptors ALK1 and ALK5 to be regulated by oxygen tension on the mRNA and protein level. In addition, expression of type III co-receptors betaglycan and endoglin appeared to be regulated by oxygen tension as well. R-Smad signaling confirmed that physoxia divergently regulated phosphorylation of Smad1/5/8 and Smad2/3. Pharmacological inhibition of canonical ALK5-mediated signaling abrogated physoxia-induced COL2A1 and PAI-1 expression. Physoxia altered expression of hypertrophy markers and that of matrix metalloproteases and their activity, as well as expression ratios of specific proteins (Sp)/Krüppel-like transcription factor family members SP1 and SP3, proving a molecular concept of ECM marker regulation. Keeping oxygen levels tightly balanced within a physiological range is important for optimal chondrocytic marker expression. Our study provides novel insights into transcriptional regulations in chondrocytes under physoxic in vitro conditions and may contribute to improving future cell-based articular cartilage repair strategies.

Download Full-text

Androgen receptor antagonists for prostate cancer therapy

Endocrine Related Cancer ◽

10.1530/erc-13-0545 ◽

2014 ◽

Vol 21 (4) ◽

pp. T105-T118 ◽

Cited By ~ 55

Author(s):

Christine Helsen ◽

Thomas Van den Broeck ◽

Arnout Voet ◽

Stefan Prekovic ◽

Hendrik Van Poppel ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Practice ◽

Androgen Receptor ◽

Metastatic Prostate Cancer ◽

Castration Resistant ◽

Androgen Action ◽

Conflicting Evidence ◽

Prostate Cancer Therapy ◽

Androgen Receptor Antagonists

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

Download Full-text