Complex dynamics of osteoclast formation and death in long-term cultures.
Complex dynamics of osteoclast formation and death in long-term cultures.
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DOI：
10.1371/journal.pone.0002104
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发表时间：
2008-05-07
期刊：
影响因子：
3.7
通讯作者：
Komarova SV
中科院分区：
文献类型：
--
作者：
Akchurin T;Aissiou T;Kemeny N;Prosk E;Nigam N;Komarova SV
破骨细胞是负责骨吸收的细胞，在退行性、代谢性和肿瘤性骨病的发生发展中起重要作用，这些疾病往往以骨微环境的持续变化为特征。我们的目的是研究破骨细胞的形成和死亡的动力学，大大超过标准方案的长度，并设计一个描述破骨形成的数学模型。RAW 264.7单核细胞在促吸收细胞因子RANKL作用下融合形成多核破骨细胞。我们发现，在长期实验中(15-26天)，破骨细胞数量的变化在不同的实验中是非常复杂和定性可变的。46个实验中有19个显示破骨细胞形成的单峰，而在27个实验中，我们观察到破骨细胞形成和死亡的连续波的发展。在用M-CSF和RANKL处理的小鼠骨髓细胞的长期培养中，证实了破骨细胞数量的周期性变化。由于破骨细胞数量变化的动力学被发现在很大程度上独立于单核细胞，所以描述破骨细胞和单核细胞变化的常微分方程组的两物种模型不能有效地概括破骨细胞数量的波动。在实验观察到从成熟破骨细胞收集的培养液抑制新鲜培养的破骨细胞生成后，我们引入了第三个变量，因子f，来描述破骨细胞衍生的抑制物。这个模型使我们能够模拟破骨细胞的振荡变化，这与因子f的振荡变化有关，而单核细胞则呈指数变化。重要的是，为了实现实验中观察到的振幅增加的振荡，我们还必须假设破骨细胞的存在刺激了破骨细胞的形成。本研究确定了破骨细胞自分泌调节在控制破骨细胞形成和死亡的长期动态中的关键作用，并描述了负反馈和正反馈介质在决定破骨细胞激活和失活的尖锐动力学中的互补作用。
Osteoclasts, cells responsible for bone resorption, contribute to the development of degenerative, metabolic and neoplastic bone diseases, which are often characterized by persistent changes in bone microenvironment. We aimed to investigate the dynamics of osteoclast formation and death in cultures that considerably exceeded the length of standard protocol and to design a mathematical model describing osteoclastogenesis. RAW 264.7 monocytic cells fuse to form multinucleated osteoclasts upon treatment with pro-resorptive cytokine RANKL. We have found that in long-term experiments (15–26 days), the dynamics of changes in osteoclast numbers was remarkably complex and qualitatively variable in different experiments. Whereas 19 of 46 experiments exhibited single peak of osteoclast formation, in 27 experiments we observed development of successive waves of osteoclast formation and death. Periodic changes in osteoclast numbers were confirmed in long-term cultures of mouse bone marrow cells treated with M-CSF and RANKL. Because the dynamics of changes in osteoclast numbers was found to be largely independent of monocytes, a two-species model of ordinary differential equations describing the changes in osteoclasts and monocytes was ineffective in recapitulating the oscillations in osteoclast numbers. Following experimental observation that medium collected from mature osteoclasts inhibited osteoclastogenesis in fresh cultures, we introduced a third variable, factor f, to describe osteoclast-derived inhibitor. This model allowed us to simulate the oscillatory changes in osteoclasts, which were coupled to oscillatory changes in the factor f, whereas monocytes changed exponentially. Importantly, to achieve the experimentally observed oscillations with increasing amplitude, we also had to assume that osteoclast presence stimulates osteoclast formation. This study identifies the critical role for osteoclast autocrine regulation in controlling long-term dynamic of osteoclast formation and death and describes the complementary roles for negative and positive feedback mediators in determining the sharp dynamics of activation and inactivation of osteoclasts.
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DOI：
10.1196/annals.1346.013
发表时间：
2006-01-01
期刊：
SKELETAL DEVELOPMENT AND REMODELING IN HEALTH, DISEASE, AND AGING
影响因子：
--
作者：
Roodman, G. David
通讯作者：
Roodman, G. David
影响因子：
2
作者：
Colijn, C;Mackey, MC
通讯作者：
Mackey, MC
影响因子：
4.1
作者：
Komarova, SV;Smith, RJ;Wahl, LM
通讯作者：
Wahl, LM
影响因子：
6.2
作者：
Quinn, JMW;Itoh, K;Gillespie, MT
通讯作者：
Gillespie, MT
影响因子：
2
作者：
Lemaire, V;Tobin, FL;Suva, LJ
通讯作者：
Suva, LJ