NELL-1 is a secreted osteoinductive protein that binds to the cell surface receptor Integrinβ1. Binding to Integrinα3 has also been reported. Multiple intracellular signaling pathways have been shown to increase after NELL-1 stimulation, including MAPK, Hedgehog, and β-catenin dependent Wnt signaling. Although the relative importance of these pathways is still undefined, NELL-1 treatment results in increased Runx2 transcription, Runx2 phosphorylation, and induction of osteogenic programming.