The effect of Irisin on bone cells in vivo and in vitro

2021 ◽  
Author(s):  
Cinzia Buccoliero ◽  
Angela Oranger ◽  
Graziana Colaianni ◽  
Patrizia Pignataro ◽  
Roberta Zerlotin ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Bone Mineral ◽  
Bone Cells ◽  
Healthy Children ◽  
Mineral Density ◽  
Skeletal Health ◽  
Bone Mineral Status

The myokine Irisin, produced during physical exercise, has an anabolic effect on bone, both in vitro and in vivo. Very recently, using a controlled in vitro 3D cell model to mimic the bone microenvironment aboard the International Space Station, it has been shown that Irisin treatment in microgravity prevents the down-regulation of the transcription factors Atf4, Runx2 and Osterix, as well as Collagen I and Osteoprotegerin proteins, crucial for osteoblast differentiation in physiologic conditions. Irisin action has also been investigated in human subjects, in which it correlates with bone health status, supporting its physiological importance also in human bone, both in healthy subjects and in patients suffering from diseases related to bone metabolism, such as hyperparathyroidism and type 1 diabetes. Low levels of circulating Irisin have been found in post-menopausal women affected by hyperparathyroidism. Furthermore, Irisin is positively correlated with bone strength in athletes and bone mineral density in football players. Moreover, in healthy children, Irisin is positively associated with bone mineral status and in children with type 1 diabetes, Irisin is positively correlated with improved glycemic control and skeletal health. In this review, we will focus on recent findings about Irisin action on microgravity induced bone loss and on osteocyte activity and survival through its αV/β5 integrin receptor.

scholarly journals Irisin and Bone: From Preclinical Studies to the Evaluation of Its Circulating Levels in Different Populations of Human Subjects

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 451 ◽  
Author(s):  
Graziana Colaianni ◽  
Lorenzo Sanesi ◽  
Giuseppina Storlino ◽  
Giacomina Brunetti ◽  
Silvia Colucci ◽  
...  
Keyword(s):  
Bone Mineral ◽  
Human Subjects ◽  
Healthy Children ◽  
Mineral Density ◽  
Bone Status ◽  
Bone Mineral Status ◽  
Menopausal Women ◽  
Different Populations ◽  
Post Menopausal

Almost four years after the discovery of the anabolic action of irisin on bone in mice, ample clinical evidence is emerging in support of its additional physiological relevance in human bone. Irisin inversely correlates with sclerostin levels in adults with prediabetes and with vertebral fragility fractures in post-menopausal women. Furthermore, in athletes we observed a positive correlation between irisin and bone mineral density at different anatomical sites. Our group also described a positive association between serum irisin and bone status in healthy children and multivariate regression analysis showed that irisin is a stronger determinant of bone mineral status than bone alkaline phosphatase. In children with type 1 diabetes mellitus, serum irisin concentrations are positively associated with bone quality and with glycemic control following continuous subcutaneous insulin infusion. Additionally, our in vitro studies suggest the existence of a negative interplay between PTH and irisin biology and these results were also supported by the observation that post-menopausal women with primary hyperparathyroidism have lower levels of irisin compared to matched controls. In this review, we will focus on recent findings about circulating level of irisin in different populations of human subjects and its correlation with their bone status.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

scholarly journals Relationship between glycemic control and OPG gene polymorphisms with lower bone mineral density in patients with type 1 Diabetes mellitus

2018 ◽  
Vol 53 (4) ◽  
Author(s):  
Melina Bezerra Loureiro ◽  
Marcela Abbott Galvão Ururahy ◽  
Karla Simone Costa de Souza ◽  
Yonara Monique da Costa Oliveira ◽  
Heglayne Pereira Vital da Silva ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Bone Mineral Density ◽  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Type 1 Diabetes Mellitus ◽  
Bone Mineral ◽  
Gene Polymorphisms ◽  
Lower Bone Mineral Density ◽  
Mineral Density

scholarly journals Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

2021 ◽  
Vol 12 ◽  
Author(s):  
Kriti Joshi ◽  
Fergus Cameron ◽  
Swasti Tiwari ◽  
Stuart I. Mannering ◽  
Andrew G. Elefanty ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stem Cell ◽  
Genetic Variants ◽  
Genetic Background ◽  
Pluripotent Stem Cell ◽  
Cell Types ◽  
Polygenic Inheritance

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.

scholarly journals Bone Mineral Density and Type 1 Diabetes in Children and Adolescents: A Meta-analysis

2021 ◽  
Author(s):  
Phoebe Loxton ◽  
Kruthika Narayan ◽  
Craig F Munns ◽  
Maria E Craig
Keyword(s):  
Bone Mineral Density ◽  
Type 1 Diabetes ◽  
Lumbar Spine ◽  
Bone Mineral ◽  
Meta Analysis ◽  
Inclusion Criteria ◽  
Mineral Density ◽  
Multiple Modalities ◽  
Meta Regression

<u>Background</u> <p>There is substantial evidence that adults with type 1 diabetes have reduced bone mineral density (BMD), however findings in youth are inconsistent.</p> <p><u>Purpose</u></p> <p>Systematic review and meta-analysis of BMD in youth with type 1 diabetes using multiple modalities: dual energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT) and/or quantitative ultrasound (QUS).</p> <p><u>Data Sources</u></p> <p>PubMed, Embase, Scopus and Web of Science from 01/01/1990 to 31/12/2020, limited to humans, without language restriction.</p> <p><u>Study Selection</u></p> <p>Inclusion criteria: cross sectional or cohort studies that included BMD measured either by DXA, pQCT and/or QUS in youth (age <20 years) with type 1 diabetes and matched controls. </p> <p><u>Data extraction</u></p> <p>Total body (TB), lumbar spine (LS) and femoral BMD (DXA); tibia, radius and lumbar spine (pQCT); and phalanx and calcaneum (QUS). Weighted mean difference (WMD) or standardized mean difference (SMD) were estimated and meta-regression was performed using age, diabetes duration and HbA1c as covariates.</p> <p><u>Data Synthesis </u></p> <p>We identified 1300 non-duplicate studies; 46 met the inclusion criteria, including 2617 cases and 3851 controls. Mean age was 12.6 ± 2.3 years. Youth with type 1 diabetes had lower BMD: TB (WMD -0.04 g/cm<sup>2</sup>, 95% CI -0.06 to -0.02, <i>P</i>=0.0006); LS (-0.02 g/cm<sup>2</sup>, -0.03 to -0.0, <i>P = 0.01</i>); femur (-0.04 g/cm<sup>2</sup>, -0.05 to -0.03, <i>P</i><0.00001); tibial trabecular (-11.32 g/cm<sup>3</sup>,-17.33 to -5.30, <i>P</i>=0.0002), radial trabecular (-0.91, -1.55 to -0.27, <i>P=0.005</i>); phalangeal (-0.32, -0.38 to -0.25, <i>P</i><0.00001) and calcaneal (SMD -0.69, -1.11 to -0.26, <i>P</i>=0.001). Using meta-regression TB BMD was associated with older age (coefficient -0.0063, -0.0095 to -0.0031, <i>P</i>=0.002), but not longer diabetes duration or HbA1c.</p> <p><u>Limitations</u></p> <p>Meta-analysis was limited by the small number of studies using QUS and pQCT and lack of use BMD z-scores in all studies. </p> <p><u>Conclusions</u></p> <p>Bone development is abnormal in youth with type 1 diabetes, assessed by multiple modalities. Routine assessment of BMD should be considered in all youth with type 1 diabetes.</p>

scholarly journals Glycosylation of CaV3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes

2020 ◽  
Vol 14 ◽  
Author(s):  
Sonja Lj. Joksimovic ◽  
J. Grayson Evans ◽  
William E. McIntire ◽  
Peihan Orestes ◽  
Paula Q. Barrett ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Adult Female ◽  
Molecular Mechanisms ◽  
Sprague Dawley ◽  
Knock Out ◽  
Peripheral Diabetic Neuropathy ◽  
Novel Treatments

Our previous studies implicated glycosylation of the CaV3.2 isoform of T-type Ca2+ channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant CaV3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our in vitro study we used whole-cell recordings of current-voltage relationships to confirm that CaV3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced in vivo by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and CaV3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the CaV3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native CaV3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in CaV3.2 channels in vivo directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.

scholarly journals Serum Levels of miR-148a and miR-21-5p Are Increased in Type 1 Diabetic Patients and Correlated with Markers of Bone Strength and Metabolism

2018 ◽  
Vol 4 (4) ◽  
pp. 37 ◽  
Author(s):  
Giuseppina E. Grieco ◽  
Dorica Cataldo ◽  
Elena Ceccarelli ◽  
Laura Nigi ◽  
Giovanna Catalano ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Type 1 Diabetes ◽  
Bone Loss ◽  
Bone Metabolism ◽  
Bone Remodeling ◽  
Bone Mineral ◽  
Bone Fragility ◽  
Bone Homeostasis ◽  
Mineral Density

Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a (p = 0.012) and miR-21-5p (p = 0.034) in sera of T1D patients vs non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values (p = 0.042) and PTH circulating levels (p = 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.

scholarly journals High-glucose-induced miR-214-3p inhibits BMSCs osteogenic differentiation in type 1 diabetes mellitus

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Rongze Wang ◽  
Yuanxu Zhang ◽  
Fujun Jin ◽  
Gongchen Li ◽  
Yao Sun ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Osteogenic Differentiation ◽  
High Glucose ◽  
Bone Homeostasis ◽  
Marrow Mesenchymal Stem Cells

Abstract Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3′-UTR of β-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.

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