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The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6
Open accessAbstract
To examine whether the transcription factor Sox9 has an essential role during the sequential steps of chondrocyte differentiation, we have used the Cre/ loxP recombination system to generate mouse embryos in which either Sox9 is missing from undifferentiated mesenchymal cells of limb buds or the Sox9 gene is inactivated after chondrogenic mesenchymal condensations. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Expression of Sox5 and Sox6 , two other Sox genes involved in chondrogenesis, was no longer detected. Moreover, expression of Runx2 , a transcription factor needed for osteoblast differentiation, was also abolished. Embryos, in which Sox9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in Sox5 ; Sox6 double-null mutant mice. Most cells were arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Furthermore, chondrocyte proliferation was severely inhibited and joint formation was defective. Although Indian hedgehog , Patched1 , parathyroid hormone-related peptide ( Pthrp ), and Pth/Pthrp receptor were expressed, their expression was down-regulated. Our experiments further suggested that Sox9 is also needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes. We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway.
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Metadata
- Authors
- Akiyama, H., Chaboissier, M.-C., Martin, J. F., Schedl, A., & de Crombrugghe, B.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2002-11-01
- Volume
- 16
- Issue
- 21
- Pages
- 2813-2828
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC187468
- OpenAlex
- W2150134228
- Semantic Scholar
- e65963187a4e29b254fc91c0e5fb771b639a3d8d
- Cited by
- 1,721
- References
- 47
- Citations by year
- 2026: 52 · 2025: 47 · 2024: 54 · 2023: 73 · 2022: 83 · 2021: 92 · 2020: 98 · 2019: 81 · 2018: 79 · 2017: 82 · 2016: 79 · 2015: 82 · 2014: 89 · 2013: 89 · 2012: 81
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- March of Dimes Foundation
- Volkswagen Foundation
- National Institutes of Health (CA-16 672, AR42919)
- National Cancer Institute (CA-16672, P30CA016672)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P01AR042919)
- National Institute of Dental and Craniofacial Research (R01DE013509, R29DE012324)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone Tumor Diagnosis and Treatments
- Keywords
- SOX9, chondrogenic differentiation, chondrogenesis, SOX5, SOX6, Runx2, chondrodysplasia, mesenchymal condensation, apoptosis, Indian hedgehog, Patched1, parathyroid hormone-related protein, chondrocyte hypertrophy, joint formation, limb development, osteogenic differentiation, Cre-loxP conditional knockout
- MeSH terms
- Animals, Cell Differentiation, Cell Division, DNA-Binding Proteins, High Mobility Group Proteins, Mutation, Nuclear Proteins, Transcription Factors, Signal Transduction, Gene Expression Regulation, Developmental, Chondrocytes, Mice, SOXD Transcription Factors, SOX9 Transcription Factor
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