scholarly journals The role of estrogens for male bone health

2009 ◽  
Vol 160 (6) ◽  
pp. 883-889 ◽  
Author(s):  
Claes Ohlsson ◽  
Liesbeth Vandenput
Keyword(s):  
Bone Mass ◽  
Bone Health ◽  
Steroid Receptors ◽  
Mediated Effects ◽  
Relative Contribution ◽  
Trabecular Bone Mass ◽  
Skeletal Homeostasis ◽  
Estrogen Effects

Sex steroids are important for the growth and maintenance of both the female and the male skeleton. However, the relative contribution of androgens versus estrogens in the regulation of the male skeleton is unclear. Experiments using mice with inactivated sex steroid receptors demonstrated that both activation of the estrogen receptor (ER)α and activation of the androgen receptor result in a stimulatory effect on both the cortical and trabecular bone mass in males. ERβ is of no importance for the skeleton in male mice while it modulates the ERα-action on bone in female mice. Previous in vitro studies suggest that the membrane G protein-coupled receptor GPR30 also might be a functional ER. Our in vivo analyses of GPR30-inactivated mice revealed no function of GPR30 for estrogen-mediated effects on bone mass but it is required for normal regulation of the growth plate and estrogen-mediated insulin-secretion. Recent clinical evidence suggests that a threshold exists for estrogen effects on bone in men: rates of bone loss and fracture risk seem to be the highest in men with estradiol levels below this threshold. Taken together, even though these findings do not exclude an important role for testosterone in male skeletal homeostasis, it is now well-established that estrogens are important regulators of bone health in men.

scholarly journals Increased Bone Mass in Mice Lacking the Adipokine Apelin

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2069-2080 ◽  
Author(s):  
Lalita Wattanachanya ◽  
Wei-Dar Lu ◽  
Ramendra K. Kundu ◽  
Liping Wang ◽  
Marcia J. Abbott ◽  
...  
Keyword(s):  
Bone Mass ◽  
Bone Cells ◽  
Physiological Role ◽  
In Vitro Study ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Primary Mouse ◽  
Skeletal Homeostasis

Abstract Adipose tissue plays an important role in skeletal homeostasis, and there is interest in identifying adipokines that influence bone mass. One such adipokine may be apelin, a ligand for the Gi-G protein-coupled receptor APJ, which has been reported to enhance mitogenesis and suppress apoptosis in MC3T3-E1 cells and primary human osteoblasts (OBs). However, it is unclear whether apelin plays a physiological role in regulating skeletal homeostasis in vivo. In this study, we compared the skeletal phenotypes of apelin knockout (APKO) and wild-type mice and investigated the direct effects of apelin on bone cells in vitro. The increased fractional cancellous bone volume at the distal femur was observed in APKO mice of both genders at 12 weeks of age and persisted until the age of 20. Cortical bone perimeter at the femoral midshaft was significantly increased in males and females at both time points. Dynamic histomorphometry revealed that APKO mice had increased rates of bone formation and mineral apposition, with evidences of accelerated OB proliferation and differentiation, without significant alteration in osteoclast activity. An in vitro study showed that apelin increased proliferation of primary mouse OBs as well as suppressed apoptosis in a dose-dependent manner with the maximum effect at 5nM. However, it had no effect on the formation of mineralized nodules. We did not observed significantly altered in osteoclast parameters in vitro. Taken together, the increased bone mass in mice lacking apelin suggested complex direct and paracrine/endocrine effects of apelin on bone, possibly via modulating insulin sensitivity. These results indicate that apelin functions as a physiologically significant antianabolic factor in bone in vivo.

scholarly journals LGR6 is necessary for attaining peak bone mass and regulates osteogenesis through differential ligand use

2021 ◽  
Author(s):  
Vikram Khedgikar ◽  
Julia F Charles ◽  
Jessica A. Lehoczky
Keyword(s):  
Bone Mass ◽  
Peak Bone Mass ◽  
Ex Vivo ◽  
Human Mesenchymal Stem Cells ◽  
Genomic Locus ◽  
Proliferation And Differentiation ◽  
Trabecular Bone Mass ◽  
G Protein Coupled

Leucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a marker of osteoprogenitor cells and is dynamically expressed during in vitro osteodifferentation of mouse and human mesenchymal stem cells (MSCs). While the Lgr6 genomic locus has been associated with osteoporosis in human cohorts, the precise molecular function of LGR6 in osteogenesis and maintenance of bone mass are not yet known. In this study, we performed in vitro Lgr6 knockdown and overexpression experiments in murine osteoblastic cells and find decreased Lgr6 levels results in reduced osteoblast proliferation, differentiation, and mineralization. Consistent with these data, overexpression of Lgr6 in these cells leads to significantly increased proliferation and osteodifferentiation. To determine whether these findings are recapitulated in vivo, we performed microCT and ex vivo osteodifferentiation analyses using our newly generated CRISPR-Cas9 mediated Lgr6 mouse knockout allele (Lgr6-KO). We find that ex vivo osteodifferentiation of Lgr6-KO primary MSCs is significantly reduced, and 8 week-old Lgr6-KO mice have less trabecular bone mass as compared to Lgr6 wildtype controls, indicating that Lgr6 is necessary for normal osteogenesis and to attain peak bone mass. Toward mechanism, we analyzed in vitro signaling in the context of two LGR6 ligands, RSPO2 and MaR1. We find that RSPO2 stimulates LGR6-mediated WNT/B-catenin signaling whereas MaR1 stimulates LGR6-mediated cAMP activity, suggesting two ligand-dependent functions for LGR6 receptor signaling during osteogenesis. Collectively, this study reveals that Lgr6 is necessary for wildtype levels of proliferation and differentiation of osteoblasts, and achieving peak bone mass.

scholarly journals Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

2020 ◽  
Vol 175 (1) ◽  
pp. 64-74 ◽  
Author(s):  
Nivedita Banerjee ◽  
Hui Wang ◽  
Gangduo Wang ◽  
M Firoze Khan
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Autoimmune Response ◽  
Mediated Effects ◽  
Antioxidant Gene Expression ◽  
Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

The Role of microRNAs in Osteoporosis Diagnostics

2021 ◽  
Vol 30 (03) ◽  
pp. 222-229
Author(s):  
Matthias Hackl ◽  
Elisabeth Semmelrock ◽  
Johannes Grillari
Keyword(s):  
Bone Mass ◽  
Bone Metabolism ◽  
Messenger Rna ◽  
Biological Fluids ◽  
Clinical Diagnostics ◽  
Bone Architecture ◽  
Estrogen Metabolism ◽  
Age Related

AbstractMicroRNAs (miRNAs) are short (18–24 nucleotides) non-coding RNA sequences that regulate gene expression via binding of messenger RNA. It is estimated that miRNAs co-regulate the expression of more than 70% of all human genes, many of which fulfil important roles in bone metabolism and muscle function. In-vitro and in-vivo experiments have shown that the targeted loss of miRNAs in distinct bone cell types (osteoblasts and osteoclasts) results in altered bone mass and bone architecture. These results emphasize the biological relevance of miRNAs for bone health.MiRNAs are not only considered as novel bone biomarkers because of their biological importance to bone metabolism, but also on the basis of other favorable properties: 1) Secretion of miRNAs from cells enables “minimally invasive” detection in biological fluids such as serum. 2) High stability of miRNAs in serum enables the retrospective analysis of frozen blood specimens. 3) Quantification of miRNAs in the serum is based on the RT-PCR - a robust method that is considered as the gold standard for the analysis of nucleic acids in clinical diagnostics.With regard to osteoporosis, it has been shown that many of the known risk factors are characterized by distinct miRNA profiles in the affected tissues: i) age-related loss of bone mass, ii) sarcopenia, iii) changes in estrogen metabolism and related changes Loss of bone mass, and iv) diabetes. Therefore, numerous studies in recent years have dealt with the characterization of miRNAs in the serum of osteoporosis patients and healthy controls, and were able to identify recurring miRNA patterns that are characteristic of osteoporosis. These novel biomarkers have great potential for the diagnosis and prognosis of osteoporosis and its clinical outcomes.The aim of this article is to give a summary of the current state of knowledge on the research and application of miRNA biomarkers in osteoporosis.

Relative Contribution of CYP3A to Amitriptyline Clearance in Humans: In Vitro and In Vivo Studies

2001 ◽  
Vol 41 (10) ◽  
pp. 1043-1054 ◽  
Author(s):  
Karthik Venkatakrishnan ◽  
Jürgen Schmider ◽  
Jerold S. Harmatz ◽  
Bruce L. Ehrenberg ◽  
Lisa L. von Moltke ◽  
...  
Keyword(s):  
In Vivo Studies ◽  
Relative Contribution

scholarly journals Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice

2021 ◽  
Vol 22 (18) ◽  
pp. 9702
Author(s):  
Ismael Y. Karkache ◽  
Jeyaram R. Damodaran ◽  
David H. H. Molstad ◽  
Kim C. Mansky ◽  
Elizabeth W. Bradley
Keyword(s):  
Bone Resorption ◽  
Bone Mass ◽  
Cell Types ◽  
Serum Markers ◽  
In Vitro Assays ◽  
Bovine Bone ◽  
Micro Computed Tomography ◽  
Myeloid Lineage ◽  
Trabecular Bone Mass

Prior work demonstrated that Phlpp1 deficiency alters trabecular bone mass and enhances M-CSF responsiveness, but the cell types and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within myeloid lineage cells, we crossed Phlpp1 floxed mice with mice harboring LysM-Cre. Micro-computed tomography of the distal femur of 12-week-old mice revealed a 30% increase in bone volume per total volume of Phlpp1 female conditional knockouts, but we did not observe significant changes within male Phlpp1 cKOLysM mice. Bone histomorphmetry of the proximal tibia further revealed that Phlpp1 cKOLysM females exhibited elevated osteoclast numbers, but conversely had reduced levels of serum markers of bone resorption as compared to littermate controls. Osteoblast number and serum markers of bone formation were unchanged. In vitro assays confirmed that Phlpp1 ablation enhanced osteoclast number and area, but limited bone resorption. Additionally, reconstitution with exogenous Phlpp1 suppressed osteoclast numbers. Dose response assays demonstrated that Phlpp1−/− cells are more responsive to M-CSF, but reconstitution with Phlpp1 abrogated this effect. Furthermore, small molecule-mediated Phlpp inhibition enhanced osteoclast numbers and size. Enhanced phosphorylation of Phlpp substrates—including Akt, ERK1/2, and PKCζ—accompanied these observations. In contrast, actin cytoskeleton disruption occurred within Phlpp inhibitor treated osteoclasts. Moreover, Phlpp inhibition reduced resorption of cells cultured on bovine bone slices in vitro. Our results demonstrate that Phlpp1 deficiency within myeloid lineage cells enhances bone mass by limiting bone resorption while leaving osteoclast numbers intact; moreover, we show that Phlpp1 represses osteoclastogenesis and controls responses to M-CSF.

scholarly journals Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses

2009 ◽  
Vol 206 (8) ◽  
pp. 1673-1680 ◽  
Author(s):  
Bart Everts ◽  
Georgia Perona-Wright ◽  
Hermelijn H. Smits ◽  
Cornelis H. Hokke ◽  
Alwin J. van der Ham ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Human Monocyte ◽  
Potent Inducer ◽  
T Helper 2 ◽  
Mediated Effects ◽  
Reporter Mice ◽  
Th2 Polarization ◽  
Th2 Responses

Soluble egg antigens of the parasitic helminth Schistosoma mansoni (S. mansoni egg antigen [SEA]) induce strong Th2 responses both in vitro and in vivo. However, the specific molecules that prime the development of Th2 responses have not been identified. We report that omega-1, a glycoprotein which is secreted from S. mansoni eggs and present in SEA, is capable of conditioning human monocyte-derived dendritic cells in vitro to drive T helper 2 (Th2) polarization with similar characteristics as whole SEA. Furthermore, using IL-4 dual reporter mice, we show that both natural and recombinant omega-1 alone are sufficient to generate Th2 responses in vivo, even in the absence of IL-4R signaling. Finally, omega-1–depleted SEA displays an impaired capacity for Th2 priming in vitro, but not in vivo, suggesting the existence of additional factors within SEA that can compensate for the omega-1–mediated effects. Collectively, we identify omega-1, a single component of SEA, as a potent inducer of Th2 responses.

scholarly journals Turnover of *I-protein C inhibitor and *I-alpha 1-antitrypsin and their complexes with activated protein C

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2290-2295 ◽  
Author(s):  
M Laurell ◽  
J Stenflo ◽  
TH Carlson
Keyword(s):  
Complex Formation ◽  
Protein C ◽  
Activated Protein C ◽  
Human Protein ◽  
Relative Contribution ◽  
Protein C Inhibitor ◽  
The Difference ◽  
Alpha 1 Antitrypsin

Abstract The rates of clearance and catabolism of human protein C inhibitor (PCI) and human alpha 1-antitrypsin (alpha 1-AT) and their complexes with human activated protein C (APC) were studied in the rabbit. The radioiodinated-free inhibitors had biologic half-lives of 23.4 and 62.1 hours, respectively, while the corresponding *I-labeled activated- protein C complexes were cleared with half-lives of 19.6 +/- 3.1 and 72.2 +/- 6.1 minutes. Complex clearances were linked to their catabolism as shown by a correlation between clearance and the appearance of free radioiodine in the plasma. Thus, the difference in the rates of catabolism would result in a fivefold greater amount of alpha 1-AT-APC complex than PCI-APC complex 1 hour after the formation of equal amounts of these in vivo. These results lead to the conclusion that the relative contribution of PCI and alpha 1-AT to the physiologic inhibition of APC cannot be determined only from the rates of the formation of these complexes in vitro, or from measurement of their levels in plasma. The APC-PCI complex is unstable as compared with the APC-alpha 1-AT complex, compounding the problem of estimating rates of complex formation from their levels in plasma.

scholarly journals Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity

2020 ◽  
Vol 21 (24) ◽  
pp. 9401
Author(s):  
Antonio Bouthelier ◽  
Florinda Meléndez-Rodríguez ◽  
Andrés A. Urrutia ◽  
Julián Aragonés
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Cellular Response ◽  
Target Gene ◽  
Target Genes ◽  
Transactivation Domain ◽  
Transactivation Domains ◽  
Relative Contribution

Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional Vhl-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as CAIX (CAR9) and BNIP3, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier SLC7A5. The HIF selectivity for some genes in WT8 cells is conserved in Vhl-deficient lung and liver tissue, whereas other genes like Glut1 (Slc2a1) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.

scholarly journals Sclareol prevents ovariectomy-induced bone loss in vivo and inhibits osteoclastogenesis in vitro via suppressing NF-κB and MAPK/ERK signaling pathways

2019 ◽  
Vol 10 (10) ◽  
pp. 6556-6567 ◽  
Author(s):  
Haiming Jin ◽  
Zhenxuan Shao ◽  
Qingqing Wang ◽  
Jiansen Miao ◽  
Xueqin Bai ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Postmenopausal Women ◽  
Postmenopausal Osteoporosis ◽  
Bone Quality ◽  
Progressive Disease ◽  
Erk Signaling ◽  
Low Bone Mass

Postmenopausal osteoporosis (PMO) is a progressive disease occurring in elderly postmenopausal women that is characterized by low bone mass and impaired bone quality.

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