Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice.
Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice.
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DOI：
10.1371/journal.pgen.1004820
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发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
de Crombrugghe B
中科院分区：
文献类型：
--
作者：
Zhou X;von der Mark K;Henry S;Norton W;Adams H;de Crombrugghe B
软骨内骨形成的关键步骤之一是用成骨细胞产生的骨小梁替代软骨细胞产生的软骨基质。然而，负责骨小梁形成的成骨细胞的确切来源尚未完全确定。为了研究肥大软骨细胞来源的细胞是否有助于小梁骨中的成骨细胞库，我们使用EGFP、LacZ或Tomato表达通过Col 10a 1-Cre或通过他莫昔芬诱导的Agc 1-CreERT 2对肥大软骨细胞进行遗传标记。两种Cre驱动程序在软骨细胞中特异性地具有活性，而在软骨膜、骨膜或任何成骨细胞谱系细胞中不具有活性。这些体内实验使我们能够跟踪Col 10a 1-Cre或Agc 1-CreERT 2表达软骨细胞中标记的细胞的命运。软骨细胞标记后，无论是在产前发育和出生后，丰富的标记非软骨细胞的细胞存在于初级海绵。这些细胞分布在整个骨小梁表面，后来出现在骨内膜中，并嵌入骨基质中。使用成骨细胞标记物的共表达研究表明，由Col 10a 1-Cre或Agc 1-CreERT 2标记的软骨细胞衍生的非软骨细胞的一部分是功能性成骨细胞。因此，我们的研究结果表明，软骨细胞在初始骨化和生长板软骨细胞出生前或出生后有能力进行转分化成为成骨细胞。来自表达Col 10a 1的肥大软骨细胞的成骨细胞约占一个月大小鼠软骨内骨中所有成熟成骨细胞的百分之六十。在成年小鼠骨折愈合过程中，软骨细胞向成骨细胞的转分化也参与了类似的过程。因此，除了骨膜中的细胞外，软骨细胞代表了体内促成软骨内骨形成的成骨细胞的主要来源。在软骨内骨形成过程中，成骨细胞存款骨特异性基质在由软骨细胞和肥大软骨细胞制成的软骨支架的表面上，软骨内骨形成负责哺乳动物和许多其他物种中的大多数骨的产生。长期以来，人们一直认为这种软骨支架中的终末分化软骨细胞经历细胞死亡。在这里，我们证明了软骨细胞可以转分化成成骨细胞，这些转分化成骨细胞代表了小鼠骨形成细胞的一个重要组成部分，我们还提供了证据，软骨细胞可以转分化成骨细胞在骨折修复过程中，一个类似于软骨内骨形成的过程。
One of the crucial steps in endochondral bone formation is the replacement of a cartilage matrix produced by chondrocytes with bone trabeculae made by osteoblasts. However, the precise sources of osteoblasts responsible for trabecular bone formation have not been fully defined. To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts. Hence, our results show that both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. Thus, in addition to cells in the periosteum chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo. During endochondral bone formation, which is responsible for the generation of most bones in mammals and many other species, osteoblasts deposit a bone-specific matrix on the surface of cartilage scaffolds made by chondrocytes and hypertrophic chondrocytes. It has long been thought that the terminally differentiated chondrocytes in this cartilage scaffold undergo cell death. Here we demonstrate that chondrocytes can transdifferentiate into osteoblasts and that these transdifferentiated osteoblasts represent a substantial fraction of the bone forming cells in mice, We also provide evidence that chondrocytes can transdifferentiate into osteoblasts during bone fracture repair, a process similar to endochondral bone formation.
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DOI：
10.1073/pnas.0504750102
发表时间：
2005-10-11
影响因子：
11.1
作者：
Akiyama, H;Kim, JE;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
64.5
作者：
Nakashima, K;Zhou, X;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
在BAC-COL10A1启动子控制下，在肥厚软骨中CRE重组酶的特异性表达。
DOI：
10.1016/j.matbio.2008.07.001
发表时间：
2008-10
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
--
作者：
Gebhard S;Hattori T;Bauer E;Schlund B;Bösl MR;de Crombrugghe B;von der Mark K
通讯作者：
von der Mark K
影响因子：
11.8
作者：
Day, TF;Guo, XZ;Yang, YZ
通讯作者：
Yang, YZ
影响因子：
4
作者：
Gerstenfeld, LC;Cullinane, DM;Einhorn, TA
通讯作者：
Einhorn, TA