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<!DOCTYPE html> <html xmlns="http://www.w3.org/1999/xhtml" lang="en" xml:lang="en" itemscope itemtype="http://schema.org/Article" class="no-js"> <head prefix="og: http://ogp.me/ns#"> <link rel="stylesheet" href="/resource/css/comments.css?79f248ebefa43b7800a14562e5049ab4"/>   <link rel="stylesheet" type="text/css" href="https://fonts.googleapis.com/css?family=Open+Sans:400,400i,600"> <link media="print" rel="stylesheet" type="text/css" href="/resource/css/print.css"/> <script type="text/javascript"> var siteUrlPrefix = "/plosone/"; </script> <script src="/resource/js/vendor/modernizr-v2.7.1.js" type="text/javascript"></script> <script src="/resource/js/vendor/detectizr.min.js" type="text/javascript"></script> <link rel="shortcut icon" href="/resource/img/favicon.ico" type="image/x-icon"/> <meta http-equiv="Content-Type" content="text/html; charset=utf-8"/> <link rel="canonical" href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204171" /> <meta name="description" content="The human skeleton undergoes constant remodeling throughout the lifetime. Processes occurring on microscopic and molecular scales degrade bone and replace it with new, fully functional tissue. Multiple bone remodeling events occur simultaneously, continuously and independently throughout the body, so that the entire 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 specialized in the resorption of old bone, others encharged with producing new bone to replace the former. These processes are tightly regulated so that the amount of new bone produced is in perfect equilibrium with that of old bone removed, thus maintaining bone microscopic structure.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, one may question whether such complexity is an inherent requirement of the process or whether some subset of the multiple constituents could fulfill the essential role, leaving functional redundancy to serve an alternative safety role. We propose in this work a minimal model of BMU function that involves a limited number of signals able to account for fully functional BMU operation. Our main assumptions were i) at any given time, any cell within a BMU can select only one among a limited choice of decisions, i.e. divide, die, migrate or differentiate, ii) this decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor are coupled to that of specific external mediators, such as hormones, cytokines, growth factors. It was thus shown that efficient BMU operation manifests as an emergent process, which results from the individual and collective decisions taken by cells within the BMU unit in the absence of any external planning." /> <meta name="citation_abstract" content="The human skeleton undergoes constant remodeling throughout the lifetime. Processes occurring on microscopic and molecular scales degrade bone and replace it with new, fully functional tissue. Multiple bone remodeling events occur simultaneously, continuously and independently throughout the body, so that the entire 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 specialized in the resorption of old bone, others encharged with producing new bone to replace the former. These processes are tightly regulated so that the amount of new bone produced is in perfect equilibrium with that of old bone removed, thus maintaining bone microscopic structure.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, one may question whether such complexity is an inherent requirement of the process or whether some subset of the multiple constituents could fulfill the essential role, leaving functional redundancy to serve an alternative safety role. We propose in this work a minimal model of BMU function that involves a limited number of signals able to account for fully functional BMU operation. Our main assumptions were i) at any given time, any cell within a BMU can select only one among a limited choice of decisions, i.e. divide, die, migrate or differentiate, ii) this decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor are coupled to that of specific external mediators, such as hormones, cytokines, growth factors. It was thus shown that efficient BMU operation manifests as an emergent process, which results from the individual and collective decisions taken by cells within the BMU unit in the absence of any external planning."> <meta name="keywords" content="Bone remodeling,Apoptosis,Osteoblasts,Osteocytes,Osteoclasts,Cell cycle and cell division,Osteoblast differentiation,Bone resorption" /> <meta name="citation_doi" content="10.1371/journal.pone.0204171"/> <meta name="citation_author" content="Clemente F. Arias"/> <meta name="citation_author_institution" content="Grupo Interdisciplinar de Sistemas Complejos (GISC), Universidad Complutense, 28040 Madrid, Spain"/> <meta name="citation_author" content="Miguel A. Herrero"/> <meta name="citation_author_institution" content="Departamento de Análisis Matemático y Matemática Aplicada, Facultad de Matemáticas, Universidad Complutense, 28040 Madrid, Spain"/> <meta name="citation_author" content="Luis F. Echeverri"/> <meta name="citation_author_institution" content="Instituto de Matemáticas, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, 53108 Medellín, Colombia"/> <meta name="citation_author" content="Gerardo E. Oleaga"/> <meta name="citation_author_institution" content="Departamento de Análisis Matemático y Matemática Aplicada, Facultad de Matemáticas, Universidad Complutense, 28040 Madrid, Spain"/> <meta name="citation_author_institution" content="Instituto de Matemática Interdisciplinar, Facultad de Matemáticas, Universidad Complutense, 28040 Madrid, Spain"/> <meta name="citation_author" content="José M. López"/> <meta name="citation_author_institution" content="Departamento de Morfología y Biología Celular, Universidad de Oviedo, 33006 Oviedo, Asturias, Spain"/> <meta name="citation_title" content="Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms"/> <meta itemprop="name" content="Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms"/> <meta name="citation_journal_title" content="PLOS ONE"/> <meta name="citation_journal_abbrev" content="PLOS ONE"/> <meta name="citation_date" content="Sep 19, 2018"/> <meta name="citation_firstpage" content="e0204171"/> <meta name="citation_issue" content="9"/> <meta name="citation_volume" content="13"/> <meta name="citation_issn" content="1932-6203"/> <meta name="citation_publisher" content="Public Library of Science"/> <meta name="citation_pdf_url" content="https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0204171&type=printable"> <meta name="citation_article_type" content="Research Article"> <meta name="dc.identifier" content="10.1371/journal.pone.0204171" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:site" content="plosone"/> <meta name="twitter:title" content="Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms" /> <meta property="twitter:description" content="The human skeleton undergoes constant remodeling throughout the lifetime. Processes occurring on microscopic and molecular scales degrade bone and replace it with new, fully functional tissue. Multiple bone remodeling events occur simultaneously, continuously and independently throughout the body, so that the entire 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 specialized in the resorption of old bone, others encharged with producing new bone to replace the former. These processes are tightly regulated so that the amount of new bone produced is in perfect equilibrium with that of old bone removed, thus maintaining bone microscopic structure.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, one may question whether such complexity is an inherent requirement of the process or whether some subset of the multiple constituents could fulfill the essential role, leaving functional redundancy to serve an alternative safety role. We propose in this work a minimal model of BMU function that involves a limited number of signals able to account for fully functional BMU operation. Our main assumptions were i) at any given time, any cell within a BMU can select only one among a limited choice of decisions, i.e. divide, die, migrate or differentiate, ii) this decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor are coupled to that of specific external mediators, such as hormones, cytokines, growth factors. It was thus shown that efficient BMU operation manifests as an emergent process, which results from the individual and collective decisions taken by cells within the BMU unit in the absence of any external planning." /> <meta property="twitter:image" content="https://journals.plos.org/plosone/article/figure/image?id=10.1371/journal.pone.0204171.g008&size=inline" /> <meta property="og:type" content="article" /> <meta property="og:url" content="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204171"/> <meta property="og:title" content="Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms"/> <meta property="og:description" content="The human skeleton undergoes constant remodeling throughout the lifetime. Processes occurring on microscopic and molecular scales degrade bone and replace it with new, fully functional tissue. Multiple bone remodeling events occur simultaneously, continuously and independently throughout the body, so that the entire 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 specialized in the resorption of old bone, others encharged with producing new bone to replace the former. These processes are tightly regulated so that the amount of new bone produced is in perfect equilibrium with that of old bone removed, thus maintaining bone microscopic structure.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, one may question whether such complexity is an inherent requirement of the process or whether some subset of the multiple constituents could fulfill the essential role, leaving functional redundancy to serve an alternative safety role. We propose in this work a minimal model of BMU function that involves a limited number of signals able to account for fully functional BMU operation. Our main assumptions were i) at any given time, any cell within a BMU can select only one among a limited choice of decisions, i.e. divide, die, migrate or differentiate, ii) this decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor are coupled to that of specific external mediators, such as hormones, cytokines, growth factors. It was thus shown that efficient BMU operation manifests as an emergent process, which results from the individual and collective decisions taken by cells within the BMU unit in the absence of any external planning."/> <meta property="og:image" content="https://journals.plos.org/plosone/article/figure/image?id=10.1371/journal.pone.0204171.g008&size=inline"/>  <script type='text/javascript'> var googletag = googletag || {}; googletag.cmd = googletag.cmd || []; (function() { var gads = document.createElement('script'); gads.async = true; gads.type = 'text/javascript'; var useSSL = 'https:' == document.location.protocol; gads.src = (useSSL ? 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Herrero,</a> <div id="author-meta-1" class="author-info" data-js-tooltip="tooltip_target"> <p class="roles" id="authRoles"> <span class="type">Roles</span> Methodology, Project administration, Supervision, Writing – review & editing </p> <p id="authAffiliations-1"><span class="type">Affiliation</span> Departamento de Análisis Matemático y Matemática Aplicada, Facultad de Matemáticas, Universidad Complutense, 28040 Madrid, Spain </p> <a data-js-tooltip="tooltip_close" class="close" id="tooltipClose1"> ⨯ </a> </div> </li> <li data-js-tooltip="tooltip_trigger" > <a data-author-id="2" class="author-name" > Luis F. Echeverri,</a> <div id="author-meta-2" class="author-info" data-js-tooltip="tooltip_target"> <p class="roles" id="authRoles"> <span class="type">Roles</span> Formal analysis, Methodology, Writing – original draft </p> <p id="authAffiliations-2"><span class="type">Affiliation</span> Instituto de Matemáticas, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, 53108 Medellín, Colombia </p> <a data-js-tooltip="tooltip_close" class="close" id="tooltipClose2"> ⨯ </a> </div> </li> <li data-js-tooltip="tooltip_trigger" > <a data-author-id="3" class="author-name" > Gerardo E. Oleaga <span class="email"> </span>,</a> <div id="author-meta-3" class="author-info" data-js-tooltip="tooltip_target"> <p class="roles" id="authRoles"> <span class="type">Roles</span> Formal analysis, Methodology, Software, Validation, Visualization </p> <p id="authCorresponding-3"> <span class="email">* E-mail:</span> <a href="mailto:goleaga@ucm.es">goleaga@ucm.es</a> (GEO); <a href="mailto:jmlopez@uniovi.es">jmlopez@uniovi.es</a> (JML)</p> <p id="authAffiliations-3"><span class="type">Affiliations</span> Departamento de Análisis Matemático y Matemática Aplicada, Facultad de Matemáticas, Universidad Complutense, 28040 Madrid, Spain, Instituto de Matemática Interdisciplinar, Facultad de Matemáticas, Universidad Complutense, 28040 Madrid, Spain </p> <div> <p class="orcid" id="authOrcid-3"> <span> <a id="connect-orcid-link" href="http://orcid.org/0000-0002-2815-8024" target="_blank" title="ORCID Registry"> <img id="orcid-id-logo" src="/resource/img/orcid_16x16.png" width="16" height="16" alt="ORCID logo"/> http://orcid.org/0000-0002-2815-8024 </a> </span> </p> </div> <a data-js-tooltip="tooltip_close" class="close" id="tooltipClose3"> ⨯ </a> </div> </li> <li data-js-tooltip="tooltip_trigger" > <a data-author-id="4" class="author-name" > José M. López <span class="email"> </span></a> <div id="author-meta-4" class="author-info" data-js-tooltip="tooltip_target"> <p class="roles" id="authRoles"> <span class="type">Roles</span> Conceptualization, Data curation, Funding acquisition, Investigation, Writing – review & editing </p> <p id="authCorresponding-4"> <span class="email">* E-mail:</span> <a href="mailto:goleaga@ucm.es">goleaga@ucm.es</a> (GEO); <a href="mailto:jmlopez@uniovi.es">jmlopez@uniovi.es</a> (JML)</p> <p id="authAffiliations-4"><span class="type">Affiliation</span> Departamento de Morfología y Biología Celular, Universidad de Oviedo, 33006 Oviedo, Asturias, Spain </p> <div> <p class="orcid" id="authOrcid-4"> <span> <a id="connect-orcid-link" href="http://orcid.org/0000-0003-0589-4763" target="_blank" title="ORCID Registry"> <img id="orcid-id-logo" src="/resource/img/orcid_16x16.png" width="16" height="16" alt="ORCID logo"/> http://orcid.org/0000-0003-0589-4763 </a> </span> </p> </div> <a data-js-tooltip="tooltip_close" class="close" id="tooltipClose4"> ⨯ </a> </div> </li> </ul> <script src="/resource/js/components/tooltip.js" type="text/javascript"></script> </div> <div id="floatTitleTop" data-js-floater="title_author" class="float-title" role="presentation"> <div class="set-grid"> <div class="float-title-inner"> <h1><?xml version="1.0" encoding="UTF-8"?>Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms</h1> <ul id="floatAuthorList" data-js-floater="floated_authors"> <li data-float-index="1">Clemente F. Arias,  </li> <li data-float-index="2">Miguel A. Herrero,  </li> <li data-float-index="3">Luis F. Echeverri,  </li> <li data-float-index="4">Gerardo E. Oleaga,  </li> <li data-float-index="5">José M. López </li> </ul> </div> <div class="logo-close" id="titleTopCloser"> <img src="/resource/img/logo-plos.png" style="height: 2em" alt="PLOS" /> <div class="close-floater" title="close">x</div> </div> </div> </div> <ul class="date-doi"> <li id="artPubDate">Published: September 19, 2018</li> <li id="artDoi"> <a href="https://doi.org/10.1371/journal.pone.0204171">https://doi.org/10.1371/journal.pone.0204171</a> </li> <li class="flex-spacer"></li> <li class="published"> <a id="preprintsLink" href="https://doi.org/10.1101/318931">See the preprint</a> </li> </ul> </div> <div> </div> </header> <section class="article-body"> <ul class="article-tabs"> <li class="tab-title " id="tabArticle"> <a href="/plosone/article?id=10.1371/journal.pone.0204171" class="article-tab-1">Article</a> </li> <li class="tab-title " id="tabAuthors"> <a href="/plosone/article/authors?id=10.1371/journal.pone.0204171" class="article-tab-2">Authors</a> </li> <li class="tab-title " id="tabMetrics"> <a href="/plosone/article/metrics?id=10.1371/journal.pone.0204171" class="article-tab-3">Metrics</a> </li> <li class="tab-title active" id="tabComments"> <a href="/plosone/article/comments?id=10.1371/journal.pone.0204171" class="article-tab-4">Comments</a> </li> <li class="tab-title" id="tabRelated"> <a class="article-tab-5" id="tabRelated-link">Media Coverage</a> <script>$(document).ready(function() { $.getMediaLink("10.1371/journal.pone.0204171").then(function (url) { $("#tabRelated-link").attr("href", url) } ) })</script> </li> </ul> <div id="thread" class="article-container"> <h2>Reader Comments (1)</h2> <p class="post_comment"> <a href="/plosone/article/comments/new?id=10.1371/journal.pone.0204171"> Post a new comment</a> on this article </p> <ul id="threads"> <li class="cf"> <div class="responses"> <span>0</span> Responses </div> <div class="recent"> 20 Nov 2018 <br/> 09:11 GMT<br/> <span>Most Recent</span> </div> <div class="title"> <a href="/plosone/article/comment?id=10.1371/annotation/43d08411-0523-49a7-96c0-485afd16bbb8"> Additional funding information </a> <span> Posted by <span class="userlink " >goleaga</span> on 20 Nov 2018 at 09:11 GMT </span> </div> </li> </ul> </div> </section> <aside class="article-aside">  <div class="dload-menu"> <div class="dload-pdf"> <a href="/plosone/article/file?id=10.1371/journal.pone.0204171&type=printable" id="downloadPdf" target="_blank">Download PDF</a> </div> <div data-js-tooltip-hover="trigger" class="dload-hover">  <ul class="dload-xml" data-js-tooltip-hover="target"> <li><a href="/plosone/article/citation?id=10.1371/journal.pone.0204171" id="downloadCitation">Citation</a></li> <li><a href="/plosone/article/file?id=10.1371/journal.pone.0204171&type=manuscript" id="downloadXml">XML</a> </li> </ul> </div> </div> <div class="aside-container"> <div class="print-article" id="printArticle" data-js-tooltip-hover="trigger"> <a href="#" onclick="window.print(); 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