81 research outputs found
The cellular dynamics of bone remodeling: a mathematical model
The mechanical properties of vertebrate bone are largely determined by a
process which involves the complex interplay of three different cell types.
This process is called {\it bone remodeling}, and occurs asynchronously at
multiple sites in the mature skeleton. The cells involved are bone resorbing
osteoclasts, bone matrix producing osteoblasts and mechanosensing osteocytes.
These cells communicate with each other by means of autocrine and paracrine
signaling factors and operate in complex entities, the so-called bone
multicellular units (BMU). To investigate the BMU dynamics in silico, we
develop a novel mathematical model resulting in a system of nonlinear partial
differential equations with time delays. The model describes the osteoblast and
osteoclast populations together with the dynamics of the key messenger molecule
RANKL and its decoy receptor OPG. Scaling theory is used to address parameter
sensitivity and predict the emergence of pathological remodeling regimes. The
model is studied numerically in one and two space dimensions using finite
difference schemes in space and explicit delay equation solvers in time. The
computational results are in agreement with in vivo observations and provide
new insights into the role of the RANKL/OPG pathway in the spatial regulation
of bone remodeling
Mathematical model of physicochemical regulation of precipitation of bone hydroxyapatite
IntroductionFormation of hydroxyapatite in bone, dentin, and enamel occurs at restricted molecular sites of specific extracellular matrix proteins and is controlled by multiple mineralization inhibitors. However, the role of physicochemical factors, such as the availability of required ions and the saturation status of the aqueous environment in biological mineralization, is not fully understood. The goal of this study was to use mathematical modeling to describe the complex physicochemical environment permissive to the precipitation of biological hydroxyapatite.MethodsWe simulated the processes occurring in the bone interstitial fluid (ISF) defined as an aqueous environment containing seven chemical components (calcium, phosphate, carbonate, sodium, potassium, magnesium, and chloride) that form 30 chemical species. We simulated reversible equilibrium reactions among these chemical species, and calculated supersaturation for hydroxyapatite and its precipitation rate using kinetic theory.Results and DiscussionThe simulated ISF was of correct ionic strength and predicted the equilibrium component concentrations that were consistent with the experimental findings. Supersaturation of physiological ISF was ~15, which is consistent with prior findings that mineralization inhibitors are required to prevent spontaneous mineral precipitation. Only total calcium, total phosphate and to a lesser degree total carbonate affected ion availability, solution supersaturation and hydroxyapatite precipitation rate. Both calcium and phosphate levels directly affected hydroxyapatite precipitation, and phosphate was affected by pH, which additionally influenced hydroxyapatite precipitation. Integrating mathematical models capturing the physiochemical and biological factors regulating bone mineralization will allow in silico studies of complex clinical scenarios associated with alterations in ISF ion composition, such as rickets, hypophosphatemia, and chronic kidney disease
Meta-Analytic Methodology for Basic Research: A Practical Guide
Basic life science literature is rich with information, however methodically quantitative attempts to organize this information are rare. Unlike clinical research, where consolidation efforts are facilitated by systematic review and meta-analysis, the basic sciences seldom use such rigorous quantitative methods. The goal of this study is to present a brief theoretical foundation, computational resources and workflow outline along with a working example for performing systematic or rapid reviews of basic research followed by meta-analysis. Conventional meta-analytic techniques are extended to accommodate methods and practices found in basic research. Emphasis is placed on handling heterogeneity that is inherently prevalent in studies that use diverse experimental designs and models. We introduce MetaLab, a meta-analytic toolbox developed in MATLAB R2016b which implements the methods described in this methodology and is provided for researchers and statisticians at Git repository (https://github.com/NMikolajewicz/MetaLab). Through the course of the manuscript, a rapid review of intracellular ATP concentrations in osteoblasts is used as an example to demonstrate workflow, intermediate and final outcomes of basic research meta-analyses. In addition, the features pertaining to larger datasets are illustrated with a systematic review of mechanically-stimulated ATP release kinetics in mammalian cells. We discuss the criteria required to ensure outcome validity, as well as exploratory methods to identify influential experimental and biological factors. Thus, meta-analyses provide informed estimates for biological outcomes and the range of their variability, which are critical for the hypothesis generation and evidence-driven design of translational studies, as well as development of computational models
Modernization of the approach to usage of region’s budget resources in the conditions of information economy development
The purpose of the article is to substantiate the necessity and to develop recommendations for modernizing the approach for usage of region’s budget resources in the conditions of the information economy creation. The methodological provision of verification of the offered hypothesis includes the specially developed method for evaluating the effectiveness of usage of region’s budget resources from the position of the information economy creation. For calculations, the article uses the information and analytical materials of the Russian specialized institutions that study the processes of development of the information economy: “Research Financial Institute”, Ministry of Communications and Mass Communications of the Russian Federation, and expert and ranking organizations – the State Management and CNews. It is proved that the traditional approach to usage of region’s budget resources, which is applied in modern Russia, contradicts the general national course for development of the information economy, as it does not stimulate the formation of information society and development of information and technological spheres of the regional economy and does not allow for development of interaction and cooperation of all interests parties within the budget process, which confirms the offered hypothesis. To solve the determined problem, the authors develop the modern approach to the usage of region’s budget resources in the conditions of the information economy creation and offer practical recommendations for modernizing the existing approach in modern Russia.peer-reviewe
Collagen type I degradation fragments act through the collagen receptor LAIR-1 to provide a negative feedback for osteoclast formation
Influence des flux de calcium sur la contrainte de cisaillement agissant sur les ostéocytes dans l'os cortical
Nous avons modélisé l'écoulement du fluide encerclant les cellules osseuses mécano-sensibles (ostéocytes). Le but de cette étude est d'améliorer nos modèles précédents en incluant des flux de calcium apparaissant lors de la dissolution ou de la précipitation de la matrice osseuse. Même si ces flux ne semblent pas altérer de manière significative la vitesse du fluide, ils peuvent changer le cisaillement ressenti par les ostéocytes. Par conséquent, nous avons examiné la façon dont de tels échanges chimiques affectent l'écoulement du fluide et donc la mécano-sensibilité des ostéocytes
Exosomal release of L-plastin by breast cancer cells facilitates metastatic bone osteolysis
Bone metastasis from breast and prostate carcinomas is facilitated by activation of bone-resorbing osteoclasts. Using proteomics approaches, we have identified peroxiredoxin-4 (PRDX4) as a cancer-secreted mediator of osteoclastogenesis. We now report characterization of L-plastin in the conditioned media (CM) of MDA-MB-231 human breast cancer cells using immunoblotting and mass spectrometry. The osteoclastogenic potential of MDAMB-231 CM with siRNA-silenced L-plastin was significantly reduced. L-plastin was detected in cancer-derived exosomes, and inhibition of exosomal release significantly decreased the osteoclastogenic capacity of MDA-MB-231 CM. When added to osteoclast precursors primed with RANKL for 2 days, recombinant L-plastin induced calcium/NFATc1-mediated osteoclastogenesis to the levels similar to continuous treatment with RANKL. Using shRNA, we generated MDA-MB-231 cells lacking L-plastin, PRDX4, or both and injected these cell populations intratibially in CD-1 immunodeficient mice. Micro-CT and histomorphometric analysis demonstrated a complete loss of osteolysis when MDA-MB-231 cells lacking both L-plastin and PRDX4 were injected. A meta-analysis established an increase in L-plastin and PRDX4 mRNA expression in numerous human cancers, including breast and prostate carcinomas. This study demonstrates that secreted L-plastin and PRDX4 mediate osteoclast activation by human breast cancer cells
ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone
INTRODUCTION: Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. METHODS: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors. RESULTS: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5. CONCLUSIONS: Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis
Intrauterine bone fractures in fetuses with osteogenesis imperfecta: a literature review and a case report
The article presents a literature review on intrauterine bone fractures in fetuses suffering from osteogenesis imperfecta. Prenatal ultrasound investigation of
the condition is made to identify pathologically changed bone tissue including shortened and deformed limb segments and ribs, bone fractures and callus
formation and widened intracranial sutures. Comprehensive clinical, paraclinical and radiological evaluations are produced after the birth to determine
treatment strategy. Skeletal fractures in newborns are treated conservatively. With diagnosis of osteogenesis imperfect established medical treatment with
bisphosphonates is administered to inhibit osteoclast-mediated bone resorption, facilitate bone mineralization and lower fracture incidence. The case report
describes fractures of both femurs and left tibia in a female newborn suffering from osteogenesis imperfecta type III diagnosed in utero with ultrasonographic
screening. The case presented highlights infant’s trauma-focused status, radiological findings and the treatment performed
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