Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

2-2018

Publication Source

American Journal of Pathology

Volume

188

Issue

2

Start Page

392

Last Page

403

DOI

10.1016/j.ajpath.2017.09.020

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

Comments

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.

Keywords

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

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Date Posted: 10 February 2023

This document has been peer reviewed.