Dataset Information

Vital Roles of ?-catenin in Trans-differentiation of Chondrocytes to Bone Cells.

ABSTRACT: A recent breakthrough showing that direct trans-differentiation of chondrocytes into bone cells commonly occurs during endochondral bone formation in the growth plate, articular cartilage, and mandibular condylar cartilage suggests that chondrogenesis and osteogenesis are likely one continuous biological process instead of two separate processes. Yet, gene regulation of this cell transformation is largely unclear. Here, we employed cartilage-specific ?-catenin loss-of-function (?-catenin fx/fx ) and gain-of-function (?-catenin fx(exon3)/ fx(exon3) ) models in the R26RTomato background (for better tracing the cell fate of chondrocytes) to study the role of ?-catenin in cell trans-differentiation. Using histological, immunohistochemical, and radiological methods combined with cell lineage tracing techniques, we showed that deletion of ?-catenin by either Acan-CreERT2 or Col10a1-Cre resulted in greatly reduced cell trans-differentiation with a significant decrease in subchondral bone volume during mandibular condylar growth. Molecular studies demonstrated severe defects in cell proliferation and differentiation in both chondrocytes and bone cells. The gain of function studies (constitutive activation of ?-catenin with Acan-CreERT2 at ages of postnatal day 7, 4-weeks and 6-months) led to more bone cell trans-differentiation of chondrocytes in the mandibular condyle due to increased proliferation and accelerated chondrocyte differentiation with incipient osteogenic changes within the cartilage matrix, resulting in an increased volume of poorly-formed immature subchondral bone. These results support the notion that chondrogenesis and osteogenesis are one continuous process, in which ?-catenin signaling plays an essential role in the cell trans-differentiation of chondrocytes into bone cells during mandibular condylar development and growth.

SUBMITTER: Jing Y

PROVIDER: S-EPMC5821044 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Vital Roles of β-catenin in Trans-differentiation of Chondrocytes to Bone Cells.

Jing Yan Y Jing Junjun J Wang Ke K Chan Kevin K Harris Stephen E SE Hinton Robert J RJ Feng Jian Q JQ

International journal of biological sciences 20180101 1

A recent breakthrough showing that direct trans-differentiation of chondrocytes into bone cells commonly occurs during endochondral bone formation in the growth plate, articular cartilage, and mandibular condylar cartilage suggests that chondrogenesis and osteogenesis are likely one continuous biological process instead of two separate processes. Yet, gene regulation of this cell transformation is largely unclear. Here, we employed cartilage-specific <i>β-catenin</i> loss-of-function (<i>β-caten ...[more]

PMID: 29483820

Similar Datasets

Project description:Dentin matrix protein 1 (DMP1) is primarily expressed in osteocytes, although a low level of DMP1 is also detected in chondrocytes. Removing Dmp1 in mice or a mutation in humans leads to hypophosphatemic rickets (identical to X-linked hypophosphatemia). The deformed skeletons were currently thought to be a consequence of an inhibition of chondrogenesis (leading to an accumulation of hypertrophic chondrocytes and a failure in the replacement of cartilage by bone). To precisely study the mechanisms by which DMP1 and phosphorus control temporomandibular condyle formation, we first showed severe malformed condylar phenotypes in Dmp1-null mice (great expansions of deformed cartilage layers and subchondral bone), which worst as aging. Next, we excluded the direct role of DMP1 in condylar hypertrophic-chondrogenesis by conditionally deleting Dmp1 in hypertrophic chondrocytes using Col10a1-Cre and Dmp1 loxP mice (displaying no apparent phosphorous changes and condylar phenotype). To address the mechanism by which the onset of endochondral phenotypes takes place, we generated two sets of tracing lines in the Dmp1 KO background: AggrecanCreERT2-ROSA-tdTomato and Col 10a1-Cre-ROSA-tdTomato, respectively. Both tracing lines displayed an acceleration of chondrogenesis and cell trans-differentiation from chondrocytes into bone cells in the Dmp1 KO. Next, we showed that administrations of neutralizing fibroblast growth factor 23 (FGF23) antibodies in Dmp1-null mice restored hypophosphatemic condylar cartilage phenotypes. In further addressing the rescue mechanism, we generated compound mice containing Col10a1-Cre with ROSA-tdTomato and Dmp1 KO lines with and without a high Pi diet starting at day 10 for 39 days. We demonstrated that hypophosphatemia leads to an acceleration of chondrogenesis and trans-differentiation of chondrocytes to bone cells, which were largely restored under a high Pi diet. Finally, we identified the causative molecule (β-catenin). Together, this study demonstrates that the Dmp1-null caused hypophosphatemia, leading to acceleration (instead of inhibition) of chondrogenesis and bone trans-differentiation from chondrocytes but inhibition of bone cell maturation due to a sharp increase in β-catenin. These findings will aid in the future treatment of hypophosphatemic rickets with FGF23 neutralizing antibodies.

Dataset Information

Vital Roles of ?-catenin in Trans-differentiation of Chondrocytes to Bone Cells.

Publications

Vital Roles of β-catenin in Trans-differentiation of Chondrocytes to Bone Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets