Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms
Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms
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DOI：
10.1371/journal.pone.0204171
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发表时间：
2018-09-19
期刊：
影响因子：
3.7
通讯作者：
Lopez, Jose M.
中科院分区：
文献类型：
--
作者：
Arias, Clemente F.;Herrero, Miguel A.;Lopez, Jose M.
人的骨骼在一生中会经历不断的重塑。在显微镜和分子尺度上发生的过程会降解骨骼，并将其替换为新的、功能齐全的组织。多个骨骼重塑事件同时、持续和独立地在全身发生，因此整个骨骼大约每十年完全更新一次。骨重建是由称为骨多细胞单位(BMU)的细胞组执行的。BMU由不同的细胞类型组成，一些细胞专门吸收旧骨，另一些细胞负责产生新骨来取代前者。这些过程受到严格的调控，以使新骨的生成量与去除的旧骨的量保持完美的平衡，从而保持骨骼的微观结构。到目前为止，许多参与骨重建的调节分子已经被确定，但BMU操作的确切机制仍未完全阐明。鉴于已知的信号通路的复杂性，人们可能会质疑这种复杂性是否是过程的内在要求，或者多个组成部分的某个子集是否可以履行基本角色，留下功能冗余来服务于替代的安全角色。在这项工作中，我们提出了一个BMU功能的最小模型，该模型涉及能够解释全功能BMU操作的有限数量的信号。我们的主要假设是：i)在任何给定的时间，BMU内的任何细胞都只能从有限的决策选择中选择一个，即分裂、死亡、迁移或分化，ii)这个决定是由适当的内部抑制物的耗尽不可逆转地决定的，iii)任何这样的抑制物的动态与特定的外部介质，如激素、细胞因子、生长因子的动态耦合。因此，有效的BMU运作表现为一个紧急的过程，这是在没有任何外部规划的情况下，BMU单元内的单元作出个人和集体决定的结果。
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.