%0 Journal Article
%T Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3¨CMediated Indian Hedgehog Signaling
%A Chenshuang Li
%A Chia Soo
%A Cymbeline T. Culiat
%A Emily A. Berthiaume
%A Eric C. Chen
%A Jie Jiang
%A Kang Ting
%A Kevin Lee
%A Wenlu Jiang
%A Xinli Zhang
%A Yan-Heng Zhou
%A Zhong Zheng
%J Archive of "The American Journal of Pathology".
%D 2018
%R 10.1016/j.ajpath.2017.09.020
%X 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)¡ªthe 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¨Cstimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine. Importantly, the authors demonstrated that Nell-1¨Cresponsive 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¨Cstimulated Ihh activation. For the first time, the Runx2¡úNell-1¡úRunx3¡úIhh 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
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785559/