Growth plate resting zone chondrocytes acquire transient clonal competency upon Hedgehog activation and efficiently transform into trabecular bone osteoblasts
The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-indian hedgehog (Ihh) feedback regulat...
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Published in | bioRxiv : the preprint server for biology |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
04.06.2023
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Online Access | Get more information |
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Summary: | The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-indian hedgehog (Ihh) feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP
resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we utilized a tamoxifen-inducible
line with
(
) floxed and tdTomato reporter alleles to specifically activate Hedgehog signaling in PTHrP
resting chondrocytes and trace the fate of their descendants. Hedgehog-activated PTHrP
chondrocytes formed large concentric clonally expanded cell populations within the resting zone ('
') and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP
cell-descendants migrated away from the growth plate and eventually transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP
skeletal stem cells. |
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