气候变化领域集成服务门户(CCPortal): SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/ osteoblastic redifferentiation

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DOI	10.1073/pnas.2019152118
	SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/ osteoblastic redifferentiation
	Haseeb A.; Kc R.; Angelozzi M.; de Charleroy C.; Rux D.; Tower R.J.; Yao L.; da Silva R.P.; Pacifici M.; Qin L.; Lefebvre V.
发表日期	2021
ISSN	00278424
卷号	118 期号:8
英文摘要	Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific (Mgp) and progenitor-specific (Nt5e and Sox4) genes. Up-regulation of osteogenic genes (Runx2, Sp7, and Postn) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cartilage; Cell differentiation; Lineage determination; SOX9; Transcriptional regulation
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180569
作者单位	Division of Orthopaedic Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104, United States; Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
推荐引用方式 GB/T 7714	Haseeb A.,Kc R.,Angelozzi M.,et al. SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/ osteoblastic redifferentiation[J],2021,118(8).
APA	Haseeb A..,Kc R..,Angelozzi M..,de Charleroy C..,Rux D..,...&Lefebvre V..(2021).SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/ osteoblastic redifferentiation.Proceedings of the National Academy of Sciences of the United States of America,118(8).
MLA	Haseeb A.,et al."SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/ osteoblastic redifferentiation".Proceedings of the National Academy of Sciences of the United States of America 118.8(2021).