| First Author | Li C | Year | 2018 |
| Journal | Am J Pathol | Volume | 188 |
| Issue | 2 | Pages | 392-403 |
| PubMed ID | 29137952 | Mgi Jnum | J:285675 |
| Mgi Id | MGI:6399984 | Doi | 10.1016/j.ajpath.2017.09.020 |
| Citation | Li C, et al. (2018) Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3-Mediated Indian Hedgehog Signaling. Am J Pathol 188(2):392-403 |
| abstractText | 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. |
