Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes
Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes
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DOI：
10.1242/dev.130807
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发表时间：
2017-01-15
期刊：
影响因子：
4.6
通讯作者：
Bahney, Chelsea S.
中科院分区：
文献类型：
--
作者：
Hu, Diane P.;Ferro, Federico;Bahney, Chelsea S.
骨折愈合主要通过软骨内骨化过程。软骨内成骨的经典模型认为，软骨细胞成熟肥大，经历凋亡，并通过侵入的骨祖细胞形成新骨。然而，最近的数据表明，软骨细胞在生长板和再生过程中转分化为成骨细胞，但调节这一过程的机制仍不清楚。在这里，我们显示了一个空间依赖性的表型重叠之间的肥大软骨细胞和成骨细胞在软骨-骨质边界的骨折骨痂，在一个区域，我们定义为过渡区（TZ）。TZ中的肥大软骨细胞激活多能性因子[Sox 2、Oct 4（Pou 5 f1）、Nanog]的表达，并且在骨折愈合期间Sox 2的条件性敲除导致骨折骨痂减少和软骨向骨转化延迟。触发多能性基因表达的信号尚不清楚，但我们证明内皮细胞条件培养基在离体骨折培养物中上调这些基因，支持转分化发生在血管系统附近的组织学证据。阐明骨折修复的细胞和分子机制对于理解某些骨折无法愈合的原因和开发新型治疗干预措施非常重要。
Fractures heal predominantly through the process of endochondral ossification. The classic model of endochondral ossification holds that chondrocytes mature to hypertrophy, undergo apoptosis and new bone forms by invading osteoprogenitors. However, recent data demonstrate that chondrocytes transdifferentiate to osteoblasts in the growth plate and during regeneration, yet the mechanism(s) regulating this process remain unknown. Here, we show a spatially-dependent phenotypic overlap between hypertrophic chondrocytes and osteoblasts at the chondro-osseous border in the fracture callus, in a region we define as the transition zone (TZ). Hypertrophic chondrocytes in the TZ activate expression of the pluripotency factors [Sox2, Oct4 (Pou5f1), Nanog], and conditional knock-out of Sox2 during fracture healing results in reduction of the fracture callus and a delay in conversion of cartilage to bone. The signal(s) triggering expression of the pluripotency genes are unknown, but we demonstrate that endothelial cell conditioned medium upregulates these genes in ex vivo fracture cultures, supporting histological evidence that transdifferentiation occurs adjacent to the vasculature. Elucidating the cellular and molecular mechanisms underlying fracture repair is important for understanding why some fractures fail to heal and for developing novel therapeutic interventions.