Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3–Mediated Indian Hedgehog Signaling

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Penn collection
Departmental Papers (Dental)
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Animals
Calcium-Binding Proteins
Cartilage
Cell Differentiation
Cells
Cultured
Chondrocytes
Chondrogenesis
Core Binding Factor Alpha 1 Subunit
Core Binding Factor Alpha 3 Subunit
Glycoproteins
Hedgehog Proteins
Mice
Knockout
Signal Transduction
cyclopamine
neural EGFL like 1 protein
regulator protein
sonic hedgehog protein
transcription factor RUNX3
unclassified drug
calcium binding protein
glycoprotein
ihh protein
mouse
Nell1 protein
mouse
Runx2 protein
mouse
Runx3 protein
mouse
sonic hedgehog protein
transcription factor RUNX2
transcription factor RUNX3
adenovirus infection
animal cell
animal experiment
Article
cartilage
cell differentiation
cell isolation
chondrocyte
chondrogenesis
controlled study
in vitro study
in vivo study
maturation
mouse
nonhuman
priority journal
protein expression
real time polymerase chain reaction
RNA interference
signal transduction
Western blotting
animal
cartilage
cell culture
chondrogenesis
cytology
deficiency
knockout mouse
physiology
signal transduction
Dentistry
Orthodontics and Orthodontology
Other Dentistry
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Li, Chenshuang
Zheng, Zhong
Jiang, Jie
Jiang, Wenlu
Lee, Kevin
Berthiaume, Emily A.
Chen, Eric C.
Culiat, Cymbeline T.
Zhou, Yan-Heng
Zhang, Xinli
Contributor
Abstract

The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)—the major regulator of chondrocyte differentiation, proliferation, and maturation. The authors’ previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, it was further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: i) Nell-1 significantly elevated Ihh signal transduction; ii) Nell-1 deficiency markedly reduced Ihh activation in chondrocytes; and iii) Nell-1–stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine. Importantly, the authors demonstrated that Nell-1–responsive Ihh signaling and chondrogenic differentiation extended to Runx2 −/− models in vitro and in vivo. In Runx2 −/− chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2 −/− chondrocytes abolished Nell-1's stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1–stimulated Ihh activation. For the first time, the Runx2→Nell-1→Runx3→Ihh signaling cascade during chondrogenic differentiation and maturation has been identified as an alternative, but critical, pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1. © 2018 American Society for Investigative Pathology

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2018-02-01
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American Journal of Pathology
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At the time of publication, author Chenshuang Li was affiliated with the School of Dentistry, University of California and the Peking University, School and Hospital of Stomatology. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
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