IDENTIFICATION OF A NOVEL TRANSCRIPTION FACTOR REQUIRED FOR OSTEOGENIC DIFFERENTIATION OF MESENCHYMAL STEM CELLS

Osteogenic differentiation is a complex and still poorly understood biological process regulated by intrinsic cellular signals and extrinsic micro-environmental cues. Following appropriate stimuli, mesenchymal stem cells (MSCs) differentiate into osteoblasts through a tightly regulated multi-step process driven by several transcription factors and characterized by the expression of a number of bone-specific proteins. Here, we describe a novel transcription factor that we named Osteoblast Inducer (ObI)-1, involved in MSC differentiation towards the osteogenic lineage. ObI-1 encodes for a nuclear protein subjected to proteasomal degradation and expressed during osteoblast differentiation both in a murine multipotent mesenchymal cell line (W20-17) and in primary murine MSCs. RNAi-mediated knockdown of ObI-1 expression significantly impairs osteoblast differentiation and matrix mineralization with reduced expression of the osteogenic markers Runx2 and osteopontin. Conversely, ObI-1 over-expression enhances osteogenic differentiation and bone-specific markers expression. ObI-1 stimulates bone morphogenetic protein (BMP)-4 expression and the consequent activation of the Smad pathway; treatment with a BMP receptor-type I antagonist completely abolishes ObI-1-mediated stimulation of osteogenic differentiation. Collectively, our findings suggest that ObI-1 modulates osteogenic differentiation, at least in part, through the BMP signaling pathway, increasing Runx2 activation and leading to osteoblast commitment and maturation.