Runx2 is essential for the transdifferentiation of chondrocytes into osteoblasts.
Runx2 is essential for the transdifferentiation of chondrocytes into osteoblasts.
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DOI：
10.1371/journal.pgen.1009169
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发表时间：
2020-11
期刊：
影响因子：
4.5
通讯作者：
Komori T
中科院分区：
文献类型：
--
作者：
Qin X;Jiang Q;Nagano K;Moriishi T;Miyazaki T;Komori H;Ito K;Mark KV;Sakane C;Kaneko H;Komori T
软骨细胞增殖并成熟为肥大软骨细胞。血管侵入软骨发生在终末肥大软骨细胞层，终末肥大软骨细胞通过凋亡或转分化成成骨细胞而死亡。Runx 2是成骨细胞分化和软骨细胞成熟所必需的。Runx 2缺陷小鼠由软骨骨骼组成，缺乏血管侵入软骨。然而，Runx 2在血管侵入软骨中的需要、软骨细胞转分化为成骨细胞的机制以及其在骨发育中的意义仍有待阐明。为了研究这些点，我们产生Runx 2fl/flCre小鼠，其中Runx 2在肥大软骨细胞中使用Col 10a 1 Cre缺失。在Runx 2fl/fl和Runx 2fl/flCre小鼠中类似地观察到血管侵入软骨。Vegfa表达在Runx 2fl/flCre小鼠的终末肥大软骨细胞中减少，但Vegfa在骨领的成骨细胞中强烈表达，表明Vegfa在骨领成骨细胞中的表达足以使血管侵入软骨。在Runx 2fl/flCre小鼠中，末端肥大软骨细胞的凋亡增加，并且其转分化中断，导致E16.5时该区域缺乏初级海绵体和成骨细胞。成骨细胞在E17.5出现在这个区域中，在没有转分化的情况下，成骨细胞的数量和初级海绵体的形成，但不是次级海绵体，达到与出生时Runx 2fl/fl小鼠相似的水平。6周龄后，Runx 2fl/fl和Runx 2fl/flCre小鼠的骨结构和体积以及所有骨组织形态学参数相似。这些发现表明，Runx 2在终末肥大软骨细胞中的表达不是血管侵入软骨所必需的，而是其存活和转分化成骨细胞所必需的，并且转分化是胚胎和新生儿阶段小梁骨形成所必需的，但不是获得正常骨结构和体积的年轻和成年小鼠。软骨细胞和成骨细胞是由骨髓间充质干细胞分化而来的不同谱系细胞，它们在不同转录因子的调控下分化。在软骨内骨发育中，软骨细胞增殖并成熟为终末分化的软骨细胞，并且在终末分化的软骨细胞层中发生血管侵入。终末分化的软骨细胞通过凋亡或转分化为成骨细胞而死亡，这有助于骨形成。然而，转分化的分子机制和生理意义仍有待阐明。Runx 2是成骨细胞分化和软骨细胞成熟的重要转录因子，被认为是血管侵入软骨所必需的。通过在分化的软骨细胞中删除Runx 2，我们阐明了Runx 2对于转分化是必需的，并且对于维持终末分化的软骨细胞的存活是必需的，但对于血管侵入软骨不是必需的。此外，我们阐明了转分化是在胚胎和新生儿阶段骨小梁形成所必需的，但它是在年轻和成年小鼠中获得正常骨结构和体积所必需的，这可能是由于软骨膜/骨膜来源的成骨细胞的主要贡献。
Chondrocytes proliferate and mature into hypertrophic chondrocytes. Vascular invasion into the cartilage occurs in the terminal hypertrophic chondrocyte layer, and terminal hypertrophic chondrocytes die by apoptosis or transdifferentiate into osteoblasts. Runx2 is essential for osteoblast differentiation and chondrocyte maturation. Runx2-deficient mice are composed of cartilaginous skeletons and lack the vascular invasion into the cartilage. However, the requirement of Runx2 in the vascular invasion into the cartilage, mechanism of chondrocyte transdifferentiation to osteoblasts, and its significance in bone development remain to be elucidated. To investigate these points, we generated Runx2fl/flCre mice, in which Runx2 was deleted in hypertrophic chondrocytes using Col10a1 Cre. Vascular invasion into the cartilage was similarly observed in Runx2fl/fl and Runx2fl/flCre mice. Vegfa expression was reduced in the terminal hypertrophic chondrocytes in Runx2fl/flCre mice, but Vegfa was strongly expressed in osteoblasts in the bone collar, suggesting that Vegfa expression in bone collar osteoblasts is sufficient for vascular invasion into the cartilage. The apoptosis of terminal hypertrophic chondrocytes was increased and their transdifferentiation was interrupted in Runx2fl/flCre mice, leading to lack of primary spongiosa and osteoblasts in the region at E16.5. The osteoblasts appeared in this region at E17.5 in the absence of transdifferentiation, and the number of osteoblasts and the formation of primary spongiosa, but not secondary spongiosa, reached to levels similar those in Runx2fl/fl mice at birth. The bone structure and volume and all bone histomophometric parameters were similar between Runx2fl/fl and Runx2fl/flCre mice after 6 weeks of age. These findings indicate that Runx2 expression in terminal hypertrophic chondrocytes is not required for vascular invasion into the cartilage, but is for their survival and transdifferentiation into osteoblasts, and that the transdifferentiation is necessary for trabecular bone formation in embryonic and neonatal stages, but not for acquiring normal bone structure and volume in young and adult mice. Chondrocytes and osteoblasts are different lineage cells, which differentiate from mesenchymal stem cells through the regulation by different transcription factors. In endochondral bone development, chondrocytes proliferate and mature to terminally differentiated chondrocytes, and vascular invasion occurs in the layer of terminally differentiated chondrocytes. Terminally differentiated chondrocytes die by apoptosis or transdifferentiate into osteoblasts, which contribute to bone formation. However, the molecular mechanism and physiological significance of the transdifferentiation remain to be clarified. Runx2 is an essential transcription factor for osteoblast differentiation and chondrocyte maturation and has been considered to be required for vascular invasion into the cartilage. By deleting Runx2 in differentiated chondrocytes, we elucidated that Runx2 is essential for the transdifferentiation and is required for maintaining the survival of terminally differentiated chondrocytes but not for vascular invasion into the cartilage. Furthermore, we clarified that the transdifferentiation is required for trabecular bone formation in embryonic and neonatal stages, but that it is dispensable for acquiring normal bone structure and volume in young and adult mice probably due to the major contribution of osteoblasts originated from perichondrium/periosteum.
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DOI：
10.1083/jcb.153.1.87
发表时间：
2001-04-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ueta C;Iwamoto M;Kanatani N;Yoshida C;Liu Y;Enomoto-Iwamoto M;Ohmori T;Enomoto H;Nakata K;Takada K;Kurisu K;Komori T
通讯作者：
Komori T
影响因子：
5.6
作者：
Komori T
通讯作者：
Komori T
DOI：
10.1002/jbmr.2740
发表时间：
2016-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Cheung WY;Fritton JC;Morgan SA;Seref-Ferlengez Z;Basta-Pljakic J;Thi MM;Suadicani SO;Spray DC;Majeska RJ;Schaffler MB
通讯作者：
Schaffler MB
影响因子：
6.2
作者：
Himeno, M;Enomoto, H;Komori, T
通讯作者：
Komori, T
影响因子：
4.6
作者：
Duan, Xuchen;Murata, Yurie;Berendsen, Agnes D.
通讯作者：
Berendsen, Agnes D.