SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification
(2010) In Development: For advances in developmental biology and stem cells 137(6). p.901-911- Abstract
SOX9 is a transcription factor of the SRY family that regulates sex determination, cartilage development and numerous other developmental events. In the foetal growth plate, Sox9 is highly expressed in chondrocytes of the proliferating and prehypertrophic zone but declines abruptly in the hypertrophic zone, suggesting that Sox9 downregulation in hypertrophic chondrocytes might be a necessary step to initiate cartilage-bone transition in the growth plate. In order to test this hypothesis, we generated transgenic mice misexpressing Sox9 in hypertrophic chondrocytes under the control of a BAC-Col10a1 promoter. The transgenic offspring showed an almost complete lack of bone marrow in newborns, owing to strongly retarded vascular invasion... (More)
SOX9 is a transcription factor of the SRY family that regulates sex determination, cartilage development and numerous other developmental events. In the foetal growth plate, Sox9 is highly expressed in chondrocytes of the proliferating and prehypertrophic zone but declines abruptly in the hypertrophic zone, suggesting that Sox9 downregulation in hypertrophic chondrocytes might be a necessary step to initiate cartilage-bone transition in the growth plate. In order to test this hypothesis, we generated transgenic mice misexpressing Sox9 in hypertrophic chondrocytes under the control of a BAC-Col10a1 promoter. The transgenic offspring showed an almost complete lack of bone marrow in newborns, owing to strongly retarded vascular invasion into hypertrophic cartilage and impaired cartilage resorption, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed high levels of Sox9 misexpression in hypertrophic chondrocytes but deficiencies of Vegfa, Mmp13, RANKL and osteopontin expression in the non-resorbed hypertrophic cartilage, indicating that Sox9 misexpression in hypertrophic chondrocytes inhibits their terminal differentiation. Searching for the molecular mechanism of SOX9-induced inhibition of cartilage vascularization, we discovered that SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification.
(Less)
- author
- publishing date
- 2010-03-15
- type
- Contribution to journal
- publication status
- published
- keywords
- BAC, Collagen X, Mmp13, Mouse, Runx2, Transgenic, Vegfa
- in
- Development: For advances in developmental biology and stem cells
- volume
- 137
- issue
- 6
- pages
- 901 - 911
- publisher
- The Company of Biologists Ltd
- external identifiers
-
- pmid:20179096
- scopus:77950345356
- ISSN
- 0950-1991
- DOI
- 10.1242/dev.045203
- language
- English
- LU publication?
- no
- id
- 338ada55-50be-4d34-8717-d11a266befde
- date added to LUP
- 2017-02-27 14:19:51
- date last changed
- 2024-04-14 05:55:07
@article{338ada55-50be-4d34-8717-d11a266befde,
abstract = {{<p>SOX9 is a transcription factor of the SRY family that regulates sex determination, cartilage development and numerous other developmental events. In the foetal growth plate, Sox9 is highly expressed in chondrocytes of the proliferating and prehypertrophic zone but declines abruptly in the hypertrophic zone, suggesting that Sox9 downregulation in hypertrophic chondrocytes might be a necessary step to initiate cartilage-bone transition in the growth plate. In order to test this hypothesis, we generated transgenic mice misexpressing Sox9 in hypertrophic chondrocytes under the control of a BAC-Col10a1 promoter. The transgenic offspring showed an almost complete lack of bone marrow in newborns, owing to strongly retarded vascular invasion into hypertrophic cartilage and impaired cartilage resorption, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed high levels of Sox9 misexpression in hypertrophic chondrocytes but deficiencies of Vegfa, Mmp13, RANKL and osteopontin expression in the non-resorbed hypertrophic cartilage, indicating that Sox9 misexpression in hypertrophic chondrocytes inhibits their terminal differentiation. Searching for the molecular mechanism of SOX9-induced inhibition of cartilage vascularization, we discovered that SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification.</p>}},
author = {{Hattori, Takako and Müller, Catharina and Gebhard, Sonja and Bauer, Eva and Pausch, Friederike and Schlund, Britta and Bösl, Michael R. and Hess, Benjamin Andreas and Surmann-Schmitt, Cordula and Von Der Mark, Helga and De Crombrugghe, Benoit and Von Der Mark, Klaus}},
issn = {{0950-1991}},
keywords = {{BAC; Collagen X; Mmp13; Mouse; Runx2; Transgenic; Vegfa}},
language = {{eng}},
month = {{03}},
number = {{6}},
pages = {{901--911}},
publisher = {{The Company of Biologists Ltd}},
series = {{Development: For advances in developmental biology and stem cells}},
title = {{SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification}},
url = {{http://dx.doi.org/10.1242/dev.045203}},
doi = {{10.1242/dev.045203}},
volume = {{137}},
year = {{2010}},
}