Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Oral Pathology and Bone Metabolism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
PLoS Genet. 2020 Nov 30;16(11):e1009169. doi: 10.1371/journal.pgen.1009169. eCollection 2020 Nov.
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.
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细胞凋亡或转分化为成骨细胞而死亡。Runx2 对于成骨细胞分化和软骨细胞成熟是必需的。Runx2 缺陷小鼠由软骨骨骼组成，缺乏血管侵入软骨。然而，Runx2 在血管侵入软骨、软骨细胞向成骨细胞转分化的机制以及其在骨骼发育中的意义仍有待阐明。为了研究这些问题，我们生成了 Runx2fl/flCre 小鼠，其中使用 Col10a1 Cre 在肥大软骨细胞中删除 Runx2。在 Runx2fl/fl 和 Runx2fl/flCre 小鼠中观察到类似的血管侵入软骨。在 Runx2fl/flCre 小鼠中，终末肥大软骨细胞中的 Vegfa 表达减少，但在骨环带中的成骨细胞中强烈表达，表明骨环带成骨细胞中的 Vegfa 表达足以进行血管侵入软骨。Runx2fl/flCre 小鼠中终末肥大软骨细胞的凋亡增加且其转分化中断，导致 E16.5 时初级松质骨和成骨细胞缺失。在 E17.5 时，该区域出现成骨细胞，而没有转分化，并且成骨细胞的数量和初级松质骨的形成，但不是次级松质骨，在出生时达到与 Runx2fl/fl 小鼠相似的水平。在 6 周龄后，Runx2fl/fl 和 Runx2fl/flCre 小鼠的骨骼结构和体积以及所有骨骼组织形态计量参数均相似。这些发现表明，终末肥大软骨细胞中 Runx2 的表达对于血管侵入软骨不是必需的，但对于其存活和向成骨细胞的转分化是必需的，并且这种转分化对于胚胎和新生儿阶段的小梁骨形成是必需的，但对于获得年轻和成年小鼠的正常骨骼结构和体积不是必需的。
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