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(American Journal of Pathology. 2006;169:903-915.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051210

Nell-1-Induced Bone Regeneration in Calvarial Defects

Tara Aghaloo^*, Catherine M. Cowan, Yu-Fen Chou, Xinli Zhang^*, Haofu Lee^*, Steve Miao^*, Nichole Hong^*, Shun’ichi Kuroda, Benjamin Wu^*, Kang Ting^*¶ and Chia Soo^||

From the Dental and Craniofacial Research Institute,^* the Departments of Bioengineering and Material Science, and the Section of Orthodontics,^¶ School of Dentistry, University of California, Los Angeles, Los Angeles, California; the Department of Plastic and Reconstructive Surgery,^|| University of Southern California, Los Angeles, California; and the Department of Structural Molecular Biology, Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan

Many craniofacial birth defects contain skeletal components requiring bone grafting. We previously identified the novel secreted osteogenic molecule NELL-1, first noted to be overexpressed during premature bone formation in calvarial sutures of craniosynostosis patients. Nell-1 overexpression significantly increases differentiation and mineralization selectively in osteoblasts, while newborn Nell-1 transgenic mice significantly increase premature bone formation in calvarial sutures. In the current study, cultured calvarial explants isolated from Nell-1 transgenic newborn mice (with mild sagittal synostosis) demonstrated continuous bone growth and overlapping sagittal sutures. Further investigation into gene expression cascades revealed that fibroblast growth factor-2 and transforming growth factor-ß1 stimulated Nell-1 expression, whereas bone morphogenetic protein (BMP)-2 had no direct effect. Additionally, Nell-1-induced osteogenesis in MC3T3-E1 osteoblasts through reduction in the expression of early up-regulated osteogenic regulators (OSX and ALP) but induction of later markers (OPN and OCN). Grafting Nell-1 protein-coated PLGA scaffolds into rat calvarial defects revealed the osteogenic potential of Nell-1 to induce bone regeneration equivalent to BMP-2, whereas immunohistochemistry indicated that Nell-1 reduced osterix-producing cells and increased bone sialoprotein, osteocalcin, and BMP-7 expression. Insights into Nell-1-regulated osteogenesis coupled with its ability to stimulate bone regeneration revealed a potential therapeutic role and an alternative to the currently accepted techniques for bone regeneration.