Growth plate-derived hedgehog-signal-responsive cells provide skeletal tissue components in growing bone
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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 Gli1CreERT2 mice line to follow the fate of hedgehog-signal-responsive cells during endochondral bone formation. Gli1CreERT2 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.
KeywordsGrowth plate Endochondral bone development Hedgehog signaling Genetic lineage tracing
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (15K08136 to R.H., 15K08426 to R.K., 16H05161 to S.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We express our appreciation to Mss. Yuki Takaoka, Chie Shiraishi, Yukimi Utsunomiya, Kyoko Shimazu, Miyako Nagao, Messrs. Tsutomu Hirata and Hitoshi Iwata for their valuable assistance.
RH and SK conceived and designed the experiments; RH performed the experiments; RH RK IY and SK analyzed the data; RH RK IY and SK contributed reagents/materials/analysis tools; RH and SK wrote the paper.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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