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Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE244884 | GEO | 2023/10/11

REPOSITORIES: GEO

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Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency.

Project description: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 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 specifically activated Hedgehog signaling in PTHrP+ resting chondrocytes and traced the fate of their descendants using a tamoxifen-inducible Pthrp-creER line with patched-1-floxed and tdTomato reporter alleles. Hedgehog-activated PTHrP+ chondrocytes formed large, concentric, clonally expanded cell populations within the resting zone ("patched roses") 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 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 potentially novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+ skeletal stem cells.

| S-EPMC10906233 | biostudies-literature

Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency [NovaA-186]

Project description:A single cell transcriptional profile of growth plate cells of the murine femur at postnatal day 36 (P36), lineage-marked by PTHrP-creER at P6

2023-10-11 | GSE244880 | GEO

Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency [NovaA-237]

Project description:A single cell transcriptional profile of growth plate cells of the murine femur at postnatal day 36 (P36), lineage-marked by PTHrP-creER at P6, Control

2023-10-11 | GSE244881 | GEO

Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency

Project description:Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency

| PRJNA1025271 | ENA

Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency [NovaA-237]

Project description:Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency [NovaA-237]

| PRJNA1025269 | ENA

Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency [NovaA-186]

Project description:Hedgehog activation promotes osteogenic fates of growth plate resting zone chondrocytes through transient clonal competency [NovaA-186]

| PRJNA1025268 | ENA

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

Project description: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 Pthlh-creER and Apc-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.

| S-EPMC8313235 | biostudies-literature

Bovine Hypertrophic Growth Plate Chondrocytes vs. Reserve Zone Chondrocytes

Project description:Growth plate chondrocytes were isolated from the distal metacarpus of young dairy cattle (all under 10 mo of age), the chondrocytes were released from the extracellular matrix by digestion with Collagenase P for 4 hours, and the various zones of the growth plate were separated by density centrifugation. The least-dense Hypertrophic Zone (HZ) cells were compared to the most-dense Reserve Zone (RZ) cells. 6 pairs of HZ vs RZ were compared by microarray.

2009-10-27 | GSE18738 | GEO

SHP2 Regulates the Osteogenic Fate of Growth Plate Hypertrophic Chondrocytes.

Project description:Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely understood. SHP2 is an ubiquitously expressed cytoplasmic protein tyrosine phosphatase. SHP2 loss-of-function mutations in chondroid cells are linked to metachondromatosis in humans and mice, suggesting a crucial role for SHP2 in the skeleton. However, the specific role of SHP2 in skeletal cells has not been elucidated. To approach this question, we ablated SHP2 in collagen 2?1(Col2?1)-Cre- and collagen 10?1(Col10?1)-Cre-expressing cells, predominantly proliferating and hypertrophic chondrocytes, using "Cre-loxP"-mediated gene excision. Mice lacking SHP2 in Col2?1-Cre-expressing cells die at mid-gestation. Postnatal SHP2 ablation in the same cell population caused dwarfism, chondrodysplasia and exostoses. In contrast, mice in which SHP2 was ablated in the Col10?1-Cre-expressing cells appeared normal but were osteopenic. Further mechanistic studies revealed that SHP2 exerted its influence partly by regulating the abundance of SOX9 in chondrocytes. Elevated and sustained SOX9 in SHP2-deficient hypertrophic chondrocytes impaired their differentiation to osteoblasts and impaired endochondral ossification. Our study uncovered an important role of SHP2 in bone development and cartilage homeostasis by influencing the osteogenic differentiation of hypertrophic chondrocytes and provided insight into the pathogenesis and potential treatment of skeletal diseases, such as osteopenia and osteoporosis.

| S-EPMC5629218 | biostudies-literature

Growth Plate Borderline Chondrocytes Behave as Transient Mesenchymal Precursor Cells.

Project description:The growth plate provides a substantial source of mesenchymal cells in the endosteal marrow space during endochondral ossification. The current model postulates that a group of chondrocytes in the hypertrophic zone can escape from apoptosis and transform into cells that eventually become osteoblasts in an area beneath the growth plate. The growth plate is composed of cells with various morphologies; particularly at the periphery of the growth plate immediately adjacent to the perichondrium are "borderline" chondrocytes, which align perpendicularly to other chondrocytes. However, in vivo cell fates of these special chondrocytes have not been revealed. Here we show that borderline chondrocytes in growth plates behave as transient mesenchymal precursor cells for osteoblasts and marrow stromal cells. A single-cell RNA-seq analysis revealed subpopulations of Col2a1-creER-marked neonatal chondrocytes and their cell type-specific markers. A tamoxifen pulse to Pthrp-creER mice in the neonatal stage (before the resting zone was formed) preferentially marked borderline chondrocytes. Following the chase, these cells marched into the nascent marrow space, expanded in the metaphyseal marrow, and became Col(2.3?kb)-GFP+ osteoblasts and Cxcl12-GFPhigh reticular stromal "CAR" cells. Interestingly, these borderline chondrocyte-derived marrow cells were short-lived, as they were significantly reduced during adulthood. These findings demonstrate based on in vivo lineage-tracing experiments that borderline chondrocytes in the peripheral growth plate are a particularly important route for producing osteoblasts and marrow stromal cells in growing murine endochondral bones. A special microenvironment neighboring the osteogenic perichondrium might endow these chondrocytes with an enhanced potential to differentiate into marrow mesenchymal cells. © 2019 American Society for Bone and Mineral Research.

| S-EPMC6697228 | biostudies-literature

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