Neural EGFL like 1 regulates cartilage maturation through runt-related transcription factor 3-mediated Indian hedgehog signaling.

In this study, we further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: [1] Nell-1 significantly elevated Ihh signal transduction, [2] Nell-1 deficiency markedly reduced Ihh activation in chondrocytes, and [3] Nell-1-stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor, cyclopamine. Importantly, we 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, we identify the Runx2→Nell-1→Runx3→Ihh signaling cascade during chondrogenic differentiation and maturation, as an alternative, but critical pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1. PMID: 29137952 [PubMed - as supplied by publisher]
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research