Haraguchi Ryuma, Kitazawa Riko, Imai Yuuki, Kitazawa Sohei
Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime, 791-0295, Japan.
Department of Diagnostic Pathology, Ehime University Hospital, Shitsukawa, Toon City, Ehime, 791-0295, Japan.
Histochem Cell Biol. 2018 Apr;149(4):365-373. doi: 10.1007/s00418-018-1641-5. Epub 2018 Jan 22.
Longitudinal bone growth progresses by continuous bone replacement of epiphyseal cartilaginous tissue, known as "growth plate", produced by columnar proliferated- and differentiated-epiphyseal chondrocytes. The endochondral ossification process at the growth plate is governed by paracrine signals secreted from terminally differentiated chondrocytes (hypertrophic chondrocytes), and hedgehog signaling is one of the best known regulatory signaling pathways in this process. Here, to investigate the developmental relationship between longitudinal endochondral bone formation and osteogenic progenitors under the influence of hedgehog signaling at the growth plate, genetic lineage tracing was carried out with the use of Gli1 mice line to follow the fate of hedgehog-signal-responsive cells during endochondral bone formation. Gli1 genetically labeled cells are detected in hypertrophic chondrocytes and osteo-progenitors at the chondro-osseous junction (COJ); these progeny then commit to the osteogenic lineage in periosteum, trabecular and cortical bone along the developing longitudinal axis. Furthermore, in ageing bone, where longitudinal bone growth ceases, hedgehog-signal responsiveness and its implication in osteogenic lineage commitment is significantly weakened. These results show, for the first time, evidence of the developmental contribution of endochondral progenitors under the influence of epiphyseal chondrocyte-derived secretory signals in longitudinally growing bone. This study provides a precise outline for assessing the skeletal lineage commitment of osteo-progenitors in response to growth-plate-derived regulatory signals during endochondral bone formation.
纵向骨生长通过不断替换骨骺软骨组织（即“生长板”）来实现，该组织由柱状增殖和分化的骨骺软骨细胞产生。生长板处的软骨内成骨过程受终末分化软骨细胞（肥大软骨细胞）分泌的旁分泌信号调控，而刺猬信号通路是此过程中最知名的调控信号通路之一。在此，为了研究在生长板处刺猬信号通路影响下纵向软骨内骨形成与成骨祖细胞之间的发育关系，利用Gli1小鼠品系进行了遗传谱系追踪，以追踪软骨内骨形成过程中刺猬信号反应性细胞的命运。在软骨-骨交界处（COJ）的肥大软骨细胞和成骨祖细胞中检测到Gli1基因标记的细胞；这些子代随后沿发育中的纵向轴在骨膜、小梁骨和皮质骨中定向分化为成骨谱系。此外，在纵向骨生长停止的老龄骨中，刺猬信号反应性及其在成骨谱系定向分化中的作用显著减弱。这些结果首次表明，在纵向生长的骨中，骨骺软骨细胞衍生的分泌信号影响下的软骨内祖细胞具有发育贡献。本研究为评估软骨内骨形成过程中，成骨祖细胞对生长板衍生调控信号作出反应时的骨骼谱系定向分化提供了精确的概述。
