Involvement of MAPK signaling molecules and Runx2 in the NELL1-induced osteoblastic differentiation

Abstract 

NELL1 is an extracellular protein inducing osteogenic differentiation and bone formation of osteoblastic cells. To elucidate the intracellular signaling cascade evoked by NELL1, we have shown that NELL1 protein transiently activates the MAPK signaling cascade, induces the phosphorylation of Runx2, and promotes the rapid intracellular accumulation of Tyr-phosphorylated proteins. Unlike BMP2, NELL1 protein does not activate the Smad signaling cascade. These findings suggest that upon binding to a specific receptor NELL1 transduces an osteogenic signal through activation of certain Tyr-kinases associated with the Ras-MAPK cascade, and finally leads to the osteogenic differentiation.

Abbreviations: hNELL1, human novel EGF-like protein 1, ECM, extracellular matrix, ALP, alkaline phosphatase, OCN, osteocalcin, Runx2, runt-related transcription factor 2, aa, amino acid residues, TSP, thrombospondin, RFC, rat fetal calvarial, OPN, osteopontin

Keywords: MAP kinase, Osteoblast, Differentiation, Bone, Tyrosine phosphorylation