A Novel HCA Framework for Simulating the Cellular Mechanisms of Bone Remodeling

2012 ◽  
Author(s):  
Charles L. Penninger ◽  
Neal M. Patel ◽  
Andrés Tovar
Keyword(s):  
Cellular Automaton ◽  
Bone Remodeling ◽  
Metabolic Diseases ◽  
Bone Cells ◽  
Cellular Level ◽  
The Body ◽  
Cellular Mechanisms ◽  
Element Analysis ◽  
Computational Framework ◽  
Treatment Protocols

Each year, bone metabolic diseases affect millions of people of all ages, genders, and races. Common diseases such as osteopenia and osteoporosis result from the disruption of the bone remodeling process and can place an individual at a serious fracture risk. Bone remodeling is the complex process by which old bone is replaced with new tissue. This process occurs continuously in the body and is carried out by bone cells that are regulated by numerous metabolic and mechanical factors. The remodeling process provides for various functions such as adaptation to mechanical loading, damage repair, and mineral homeostasis. An improved understanding of this process is necessary to identify patients at risk of bone disease and to assess appropriate treatment protocols. High-fidelity computer models are needed to understand the complex interaction of all parameters involved in bone remodeling. The primary focus of this investigation is to present a new computational framework that utilizes mathematical rules to mechanistically model the cellular mechanisms involved in the bone remodeling process. The computational framework used in this research combines accepted biological principles, cellular-level rules in a cellular automaton framework, and finite-element analysis. This computational model is referred to as hybrid cellular automaton (HCA) model. The simulations obtained with the HCA model allow to predict time-dependent morphology variations at the tissue level as a result of biological changes at the cellular level.

scholarly journals Role of Metabolism in Bone Development and Homeostasis

2020 ◽  
Vol 21 (23) ◽  
pp. 8992
Author(s):  
Akiko Suzuki ◽  
Mina Minamide ◽  
Chihiro Iwaya ◽  
Kenichi Ogata ◽  
Junichi Iwata
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Diseases ◽  
Bone Cells ◽  
Bone Development ◽  
Bone Matrix ◽  
The Body ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Cellular Dysfunction

Carbohydrates, fats, and proteins are the underlying energy sources for animals and are catabolized through specific biochemical cascades involving numerous enzymes. The catabolites and metabolites in these metabolic pathways are crucial for many cellular functions; therefore, an imbalance and/or dysregulation of these pathways causes cellular dysfunction, resulting in various metabolic diseases. Bone, a highly mineralized organ that serves as a skeleton of the body, undergoes continuous active turnover, which is required for the maintenance of healthy bony components through the deposition and resorption of bone matrix and minerals. This highly coordinated event is regulated throughout life by bone cells such as osteoblasts, osteoclasts, and osteocytes, and requires synchronized activities from different metabolic pathways. Here, we aim to provide a comprehensive review of the cellular metabolism involved in bone development and homeostasis, as revealed by mouse genetic studies.

scholarly journals Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms

2018 ◽  
Author(s):  
Clemente F. Arias ◽  
Miguel A. Herrero ◽  
Luis F. Echeverri ◽  
Gerardo E. Oleaga ◽  
José M. López
Keyword(s):  
Signaling Pathways ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Large Degree ◽  
Cell Types ◽  
Tissue Level ◽  
The Body ◽  
Human Skeleton ◽  
Individual Decisions ◽  
Single Bone

AbstractHuman skeleton undergoes constant remodeling during the whole life. By means of such process, which occurs at a microscopic scale, worn out bone is replaced by new, fully functional one. Multiple bone remodeling events occur simultaneously and independently throughout the body, so the whole skeleton is completely renewed about every ten years.Bone remodeling is performed by groups of cells called Bone Multicellular Units (BMU). BMUs consist of different cell types; some are specialized in destroying old bone, whereas others produce new bone to replace the former. The whole process is tightly regulated so that the amount of new bone produced exactly balances that of old one removed and bone microscopic structure is maintained.To date, many regulatory molecules involved in bone remodeling have been identified, but the precise mechanism of BMU operation remains to be fully elucidated. Given the complexity of the signaling pathways already known, the question arises of ascertaining whether such complexity is an inherent requirement of the process, or a consequence of operational redundancy.In this work we propose a minimal model of BMU function which involves a small number of signals and accounts for fully functional BMU operation. Our main assumptions are i) at any given time, any cell within a BMU can select only one among a reduced choice of decisions: divide, die, migrate or differentiate, ii) such decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor is coupled to that of a few external mediators. It is shown that efficient BMU operation then unfolds as an emergent property, which results from individual decisions taken by cells in the BMU unit in the absence of any external planning.Author summaryOur skeleton is a living organ that is being renewed throughout our life. This task is accomplished by teams of bone cells termed as Bone Multicellular Units (BMUs) that are recruited when and where needed, to operate at places where bone has lost functionality either for an excess of mechanical stress or because loss of activity. Once assembled, BMU remove old bone and replace it by new one, and disband as soon as their mission has been accomplished. No single bone evades BMU screening, so that the whole human skeleton is completely renewed approximately every ten years.It is natural to wonder how such robust and fascinating process is regulated. Many signaling pathways involved in bone remodeling have been identified so far, but whether all of them are necessary for BMU operation remains unclear. In this work we show that just a reduced number of such signals could suffice for that purpose. This suggests that a large degree of redundancy might have been kept in place, perhaps as a consequence of different convergent strategies developed in the course of evolution.

Flavonoids in adipose tissue inflammation and atherosclerosis: one arrow, two targets

2020 ◽  
Vol 134 (12) ◽  
pp. 1403-1432 ◽  
Author(s):  
Manal Muin Fardoun ◽  
Dina Maaliki ◽  
Nabil Halabi ◽  
Rabah Iratni ◽  
Alessandra Bitto ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fruits And Vegetables ◽  
Metabolic Diseases ◽  
Therapeutic Agents ◽  
Adipose Tissue Inflammation ◽  
Cellular Mechanisms ◽  
Tissue Inflammation ◽  
Cholesterol Levels ◽  
Naturally Occurring ◽  
Pro Inflammatory Cytokines

Abstract Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.

Roux-en-Y Gastrointestinal Bypass Promotes Activation of TGR5 and Peptide YY

2020 ◽  
Vol 20 (8) ◽  
pp. 1262-1267
Author(s):  
Haojun Yang ◽  
Hanyang Liu ◽  
YuWen Jiao ◽  
Jun Qian
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Metabolic Diseases ◽  
Peptide Yy ◽  
The Body ◽  
Wild Type ◽  
L Cells ◽  
Body Weights ◽  
Gastrointestinal Bypass ◽  
G Protein Coupled

Background: G protein-coupled bile acid receptor (TGR5) is involved in a number of metabolic diseases. The aim of this study was to identify the role of TGR5 after Roux-en-Y gastric bypass (GBP). Methods: Wild type and TGR5 knockout mice (tgr5-/-) were fed a high-fat diet (HFD) to establish the obesity model. GBP was performed. The changes in body weight and food intake were measured. The levels of TGR5 and peptide YY (PYY) were evaluated by RT-PCR, Western blot, and ELISA. Moreover, the L-cells were separated from wild type and tgr5-/- mice. The levels of PYY in L-cells were evaluated by ELISA. Results: The body weights were significantly decreased after GBP in wild type mice (p<0.05), but not tgr5-/- mice (p>0.05). Food intake was reduced after GBP in wild type mice, but also not significantly affected in tgr5-/- mice (p>0.05). The levels of PYY were significantly increased after GBP compared with the sham group (p<0.05); however, in tgr5-/- mice the expression of PYY was not significantly affected (p>0.05). After INT-777 stimulation in L-cells obtained from murine intestines, the levels of PYY were significantly increased in L-cells tgr5+/+ (p<0.05). Conclusion: Our study suggests that GBP up-regulated the expression of TGR5 in murine intestines, and increased the levels of PYY, which further reduced food intake and decreased the body weight.

scholarly journals Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 414
Author(s):  
Saja Baraghithy ◽  
Yael Soae ◽  
Dekel Assaf ◽  
Liad Hinden ◽  
Shiran Udi ◽  
...  
Keyword(s):  
Bone Mass ◽  
Proximal Tubule ◽  
Bone Remodeling ◽  
Kidney Function ◽  
Bone Cells ◽  
Critical Role ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cell ◽  
Protective Effects ◽  
Cannabinoid 1 Receptor

The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.

scholarly journals Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III

2021 ◽  
Author(s):  
Giorgia Di Lorenzo ◽  
Lena M. Westermann ◽  
Timur A. Yorgan ◽  
Julian Stürznickel ◽  
Nataniel F. Ludwig ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Collagen Crosslinks ◽  
Clinical Criteria ◽  
Pathogenic Variants ◽  
Bone Biopsies ◽  
Appropriate Therapy ◽  
Alpha Beta ◽  
Deficient Mice

Abstract Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgkoand Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

scholarly journals Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2474
Author(s):  
Lyudmila V. Gromova ◽  
Serguei O. Fetissov ◽  
Andrey A. Gruzdkov
Keyword(s):  
Small Intestine ◽  
Blood Glucose ◽  
Metabolic Diseases ◽  
Glucose Absorption ◽  
Cellular Mechanisms ◽  
Physiological Conditions ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
New Strategy ◽  
Intestinal Glucose Absorption

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.

scholarly journals The Development of Molecular Biology of Osteoporosis

2021 ◽  
Vol 22 (15) ◽  
pp. 8182
Author(s):  
Yongguang Gao ◽  
Suryaji Patil ◽  
Jingxian Jia
Keyword(s):  
Bone Resorption ◽  
Molecular Biology ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Cell Activity ◽  
Bone Cell ◽  
Bone Disorders ◽  
Molecular Aspects

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.

scholarly journals Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

2020 ◽  
Author(s):  
Minsoo Kang ◽  
Sun Kyoung Han ◽  
Suhyun Kim ◽  
Sungyeon Park ◽  
Yerin Jo ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Metabolism ◽  
Metabolic Disorder ◽  
Leucine Zipper ◽  
Metabolic Diseases ◽  
Adenosine Monophosphate ◽  
The Body ◽  
Hepatic Gluconeogenesis ◽  
Leucine Zipper Protein

Abstract Hepatic gluconeogenesis is the central pathway for glucose generation in the body. The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Small leucine zipper protein (sLZIP) is an isoform of LZIP and it mainly functions as a transcription factor. Although sLZIP is known to regulate the transcription of genes involved in various cellular processes, the role of sLZIP in hepatic glucose metabolism is not known. In this study, we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder. We found that sLZIP expression was elevated during glucose starvation, leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes. However, sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions. sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells. Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation. Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism. These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

Simulation and Analysis on Pressure Resistance Experiments of Automotive Body

2012 ◽  
Vol 490-495 ◽  
pp. 1451-1455
Author(s):  
Guang Yao Zhao ◽  
Yi Feng Zhao ◽  
Chuan Yin Tang ◽  
Zhi Yuan Du
Keyword(s):  
Energy Absorption ◽  
The Body ◽  
Original Design ◽  
Element Analysis ◽  
Vehicle Simulation ◽  
Automotive Body ◽  
Safety Regulations ◽  
Vehicle Rollover ◽  
Pressure Resistance ◽  
Body Energy

Aimed at SUV-type vehicle, simulation and analysis of pressure resistance experiments on the body of automobile has been presented in the paper, according to the vehicle safety regulations and standards of FMVSS216. A limited SUV vehicle model is created; simulation is obtained with the help of software LS-DYNA, based on the principle of finite element analysis method. Assessment of pressure resistance and safety of the automobile has been presented, from the aspect of the deformation of body, the energy absorption of the vehicle and components, and the pressure on the body, etc. By rational improving of the original design of body structure, the reasonable distribution of pressure absorbability of the body of the SUV-type automobile is achieved. The effect of the overall energy absorption of the body is fully exerted, and then the safety of the driver and the passenger in a rollover accident is improved. Research methods and conclusions of this paper provide useful ways and references to the research of the safety of vehicle rollover and design of rationality of body energy absorption

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