Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment

• Published in: eLife Vol. 10
• Main Authors: Hallett, Shawn A, Matsushita, Yuki, Ono, Wanida, Sakagami, Naoko, Mizuhashi, Koji, Tokavanich, Nicha, Nagata, Mizuki, Zhou, Annabelle, Hirai, Takao, Kronenberg, Henry M, Ono, Noriaki
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 26.07.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Analysis; Animals; Antibiotics; bone; cartilage; Cell cycle; Cell Differentiation; Cell division; chondrocyte; Chondrocytes; Chondrocytes - cytology; Chondrocytes - metabolism; Developmental Biology; Doxycycline; Growth; Growth plate; Growth Plate - cytology; Growth Plate - metabolism; Histones; Mice; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - metabolism; Retention; skeletal stem cells; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Tetracycline; Tetracyclines; Wnt protein; wnt signaling; Wnt Signaling Pathway - physiology; β-Catenin; mouse; wnt signaling; chondrocyte; developmental biology; cartilage; bone; skeletal stem cells; growth plate
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.64513

Chondrocytes in the resting zone of the postnatal growth plate are characterized by slow cell cycle progression, and encompass a population of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem cells that contribute to the formation of columnar chondrocytes. However, how these chondrocytes are maintained in the resting zone remains undefined. We undertook a genetic pulse-chase approach to isolate slow cycling, label-retaining chondrocytes (LRCs) using a chondrocyte-specific doxycycline-controllable Tet-Off system regulating expression of histone 2B-linked GFP. Comparative RNA-seq analysis identified significant enrichment of inhibitors and activators for Wnt signaling in LRCs and non-LRCs, respectively. Activation of Wnt/β-catenin signaling in PTHrP resting chondrocytes using and -floxed allele impaired their ability to form columnar chondrocytes. Therefore, slow-cycling chondrocytes are maintained in a Wnt-inhibitory environment within the resting zone, unraveling a novel mechanism regulating maintenance and differentiation of PTHrP skeletal stem cells of the postnatal growth plate.